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    IKBKB inhibitor of nuclear factor kappa B kinase subunit beta [ Homo sapiens (human) ]

    Gene ID: 3551, updated on 3-May-2024

    Summary

    Official Symbol
    IKBKBprovided by HGNC
    Official Full Name
    inhibitor of nuclear factor kappa B kinase subunit betaprovided by HGNC
    Primary source
    HGNC:HGNC:5960
    See related
    Ensembl:ENSG00000104365 MIM:603258; AllianceGenome:HGNC:5960
    Gene type
    protein coding
    RefSeq status
    REVIEWED
    Organism
    Homo sapiens
    Lineage
    Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
    Also known as
    IKK2; IKKB; IKK-2; IMD15; IMD15A; IMD15B; NFKBIKB; IKK-beta
    Summary
    The protein encoded by this gene phosphorylates the inhibitor in the inhibitor/NF-kappa-B complex, causing dissociation of the inhibitor and activation of NF-kappa-B. The encoded protein itself is found in a complex of proteins. Several transcript variants, some protein-coding and some not, have been found for this gene. [provided by RefSeq, Sep 2011]
    Expression
    Ubiquitous expression in spleen (RPKM 14.6), lymph node (RPKM 12.4) and 25 other tissues See more
    Orthologs
    NEW
    Try the new Gene table
    Try the new Transcript table

    Genomic context

    Location:
    8p11.21
    Exon count:
    24
    Annotation release Status Assembly Chr Location
    RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 8 NC_000008.11 (42271302..42332460)
    RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 8 NC_060932.1 (42545654..42606501)
    105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 8 NC_000008.10 (42128820..42189978)

    Chromosome 8 - NC_000008.11Genomic Context describing neighboring genes Neighboring gene small nucleolar RNA U13 Neighboring gene IKBKB divergent transcript Neighboring gene ATAC-STARR-seq lymphoblastoid active region 27303 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 27304 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr8:42127815-42128314 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 19154 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 27305 Neighboring gene CDK7 strongly-dependent group 2 enhancer GRCh37_chr8:42150166-42151365 Neighboring gene uncharacterized LOC105379395 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr8:42163399-42164071 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr8:42164072-42164743 Neighboring gene H3K27ac hESC enhancer GRCh37_chr8:42179455-42179956 Neighboring gene H3K27ac hESC enhancer GRCh37_chr8:42179957-42180456 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr8:42188156-42188656 Neighboring gene ribosomal protein L5 pseudogene 23 Neighboring gene DNA polymerase beta Neighboring gene dickkopf WNT signaling pathway inhibitor 4

    Genomic regions, transcripts, and products

    Expression

    • Project title: HPA RNA-seq normal tissues
    • Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
    • BioProject: PRJEB4337
    • Publication: PMID 24309898
    • Analysis date: Wed Apr 4 07:08:55 2018

    Bibliography

    GeneRIFs: Gene References Into Functions

    What's a GeneRIF?

    HIV-1 interactions

    Protein interactions

    Protein Gene Interaction Pubs
    Envelope surface glycoprotein gp120 env HIV-1 JRFL (gp120) degrades IkappaBeta Kinases (IkB) in RPE cells PubMed
    env HIV-1 gp120/CD4 interaction-induced NF-kappaB activation stimulates the hyperphosphorylation of IkappaB-alpha by IkappaB kinases (IKKs) PubMed
    Nef nef HIV-1 Nef induces phosphorylation of IKBKB (IKK2) PubMed
    nef HIV-1 and SIVcpz Nef proteins enhance TNF-alpha, IKK-beta, and RelA/p65-induced NF-kappaB activation in 293T cells PubMed
    nef HIV-1 Nef-induced strong activation of MAP kinases (p38/MAPK14, JNK/MAPK8, and ERK1/2) and NF-kappaB pathway (IKK alpha/beta) in M2-macrophages is mediated by TAK1 PubMed
    nef The interaction of HIV-1 Nef with TRAF2, TRAF5, and TRAF6 proteins activates NF-kappaB, leading to the degradation of IkappaB-alpha and the increased phosphorylation of IKK-alpha and IKK-beta in monocyte-derived macrophages PubMed
    nef HIV-1 Nef myristoylation is required for the rapid and transient phosphorylation of the alpha- and beta- subunits of the Ikappa-B kinase complex and activation of JNK, ERK1/2 and p38 MAPK family members PubMed
    Tat tat HIV-1 Tat induces phosphorylation of IKBKB (IKK2) in CRT-MG human astroglioma cells PubMed
    tat Curcumin and celastrol attenuate HIV-1 Tat-induced p65/NFKappaB phosphorylation and IKK phosphorylation PubMed
    tat HIV-1 Tat-mediated upregulation of ICAM-1 expression involves MEK1/2, JNK, and p38 MAPK proteins and downstream IKK2/NF-kappaB signaling pathways PubMed
    tat Nox2 is involved in HIV-1 Tat-induced NADPH oxidase p65 and IKK phosphorylation PubMed
    Vpr vpr HIV-1 Vpr requires CHUK (IKKa) or IKBKB (IKKb) to induce G2/M arrest in HeLa cells as shown through siRNA knockdown of each PubMed
    vpr Activation of TAK1 by HIV-1 Vpr leads to increased levels of phosphorylated IKK-beta and MKK7 in cells PubMed
    Vpu vpu Most HIV-1 and primate lentiviral Vpu proteins inhibit IKK-beta-induced NF-kappaB activation except HIV-1 group N Vpu proteins PubMed

    Go to the HIV-1, Human Interaction Database

    Pathways from PubChem

    Interactions

    Products Interactant Other Gene Complex Source Pubs Description

    General gene information

    Markers

    Clone Names

    • FLJ33771, FLJ36218, FLJ38368, FLJ40509, MGC131801

    Gene Ontology Provided by GOA

    Function Evidence Code Pubs
    enables ATP binding IEA
    Inferred from Electronic Annotation
    more info
     
    enables IkappaB kinase activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    enables IkappaB kinase activity TAS
    Traceable Author Statement
    more info
    PubMed 
    enables identical protein binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables protein binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables protein heterodimerization activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    enables protein homodimerization activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    enables protein kinase activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    enables protein kinase binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    enables protein serine kinase activity IEA
    Inferred from Electronic Annotation
    more info
     
    enables protein serine/threonine kinase activity EXP
    Inferred from Experiment
    more info
    PubMed 
    enables protein serine/threonine kinase activity IBA
    Inferred from Biological aspect of Ancestor
    more info
     
    enables protein serine/threonine kinase activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    enables protein serine/threonine kinase activity TAS
    Traceable Author Statement
    more info
     
    enables scaffold protein binding IDA
    Inferred from Direct Assay
    more info
    PubMed 
    enables transferrin receptor binding IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    Process Evidence Code Pubs
    involved_in Fc-epsilon receptor signaling pathway TAS
    Traceable Author Statement
    more info
     
    involved_in MyD88-dependent toll-like receptor signaling pathway TAS
    Traceable Author Statement
    more info
     
    involved_in T cell receptor signaling pathway TAS
    Traceable Author Statement
    more info
     
    involved_in TRIF-dependent toll-like receptor signaling pathway TAS
    Traceable Author Statement
    more info
     
    involved_in antigen processing and presentation of exogenous peptide antigen via MHC class I, TAP-dependent TAS
    Traceable Author Statement
    more info
     
    involved_in canonical NF-kappaB signal transduction IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in canonical NF-kappaB signal transduction IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in canonical NF-kappaB signal transduction TAS
    Traceable Author Statement
    more info
    PubMed 
    involved_in cellular response to tumor necrosis factor IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in cortical actin cytoskeleton organization IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in inflammatory response TAS
    Traceable Author Statement
    more info
    PubMed 
    involved_in innate immune response TAS
    Traceable Author Statement
    more info
    PubMed 
    involved_in interleukin-1-mediated signaling pathway IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in interleukin-1-mediated signaling pathway TAS
    Traceable Author Statement
    more info
     
    involved_in negative regulation of bicellular tight junction assembly IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in negative regulation of myosin-light-chain-phosphatase activity IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in peptidyl-serine phosphorylation IBA
    Inferred from Biological aspect of Ancestor
    more info
     
    involved_in peptidyl-serine phosphorylation IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in positive regulation of DNA-templated transcription NAS
    Non-traceable Author Statement
    more info
    PubMed 
    involved_in positive regulation of NF-kappaB transcription factor activity IBA
    Inferred from Biological aspect of Ancestor
    more info
     
    acts_upstream_of_or_within positive regulation of NF-kappaB transcription factor activity IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in positive regulation of NF-kappaB transcription factor activity TAS
    Traceable Author Statement
    more info
    PubMed 
    involved_in positive regulation of canonical NF-kappaB signal transduction IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in positive regulation of canonical NF-kappaB signal transduction IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in positive regulation of transcription by RNA polymerase II IBA
    Inferred from Biological aspect of Ancestor
    more info
     
    involved_in positive regulation of transcription by RNA polymerase II IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in protein localization to plasma membrane IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in protein maturation IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in protein phosphorylation IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in protein phosphorylation NAS
    Non-traceable Author Statement
    more info
    PubMed 
    involved_in regulation of establishment of endothelial barrier IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    involved_in regulation of phosphorylation IDA
    Inferred from Direct Assay
    more info
    PubMed 
    involved_in regulation of tumor necrosis factor-mediated signaling pathway TAS
    Traceable Author Statement
    more info
     
    involved_in response to virus TAS
    Traceable Author Statement
    more info
    PubMed 
    involved_in stimulatory C-type lectin receptor signaling pathway TAS
    Traceable Author Statement
    more info
     
    involved_in stress-activated MAPK cascade TAS
    Traceable Author Statement
    more info
     
    involved_in toll-like receptor 3 signaling pathway TAS
    Traceable Author Statement
    more info
     
    involved_in tumor necrosis factor-mediated signaling pathway IBA
    Inferred from Biological aspect of Ancestor
    more info
     
    involved_in tumor necrosis factor-mediated signaling pathway IMP
    Inferred from Mutant Phenotype
    more info
    PubMed 
    Component Evidence Code Pubs
    part_of CD40 receptor complex ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    part_of IkappaB kinase complex IBA
    Inferred from Biological aspect of Ancestor
    more info
     
    part_of IkappaB kinase complex IPI
    Inferred from Physical Interaction
    more info
    PubMed 
    part_of IkappaB kinase complex TAS
    Traceable Author Statement
    more info
    PubMed 
    is_active_in cytoplasm IBA
    Inferred from Biological aspect of Ancestor
    more info
     
    is_active_in cytoplasm IDA
    Inferred from Direct Assay
    more info
    PubMed 
    located_in cytoplasmic side of plasma membrane ISS
    Inferred from Sequence or Structural Similarity
    more info
     
    located_in cytosol IDA
    Inferred from Direct Assay
    more info
     
    located_in cytosol TAS
    Traceable Author Statement
    more info
     
    located_in membrane raft IEA
    Inferred from Electronic Annotation
    more info
     
    located_in nucleus IEA
    Inferred from Electronic Annotation
    more info
     

    General protein information

    Preferred Names
    inhibitor of nuclear factor kappa-B kinase subunit beta
    Names
    I-kappa-B kinase 2
    I-kappa-B-kinase beta
    inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase beta
    nuclear factor NF-kappa-B inhibitor kinase beta
    nuclear factor kappa B kinase subunit beta
    serine/threonine protein kinase IKBKB
    NP_001177649.2
    NP_001229707.1
    NP_001547.1
    XP_011542819.1
    XP_011542822.1
    XP_047277713.1
    XP_047277714.1
    XP_047277715.1
    XP_047277716.1
    XP_047277717.1
    XP_047277718.1
    XP_047277719.1
    XP_047277720.1
    XP_054216402.1
    XP_054216403.1
    XP_054216404.1
    XP_054216405.1
    XP_054216406.1
    XP_054216407.1
    XP_054216408.1
    XP_054216409.1
    XP_054216410.1
    XP_054216411.1

    NCBI Reference Sequences (RefSeq)

    NEW Try the new Transcript table

    RefSeqs maintained independently of Annotated Genomes

    These reference sequences exist independently of genome builds. Explain

    These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

    Genomic

    1. NG_041793.1 RefSeqGene

      Range
      5001..66159
      Download
      GenBank, FASTA, Sequence Viewer (Graphics), LRG_1241

    mRNA and Protein(s)

    1. NM_001190720.3NP_001177649.2  inhibitor of nuclear factor kappa-B kinase subunit beta isoform 2

      Status: REVIEWED

      Description
      Transcript Variant: This variant (2) lacks an exon in the 5' region, resulting in an upstream AUG start codon, as compared to variant 1. The resulting isoform (2) is slightly shorter and has a different N-terminus, as compared to isoform 1.
      Source sequence(s)
      AC083973, AK091297, AK302723
      Consensus CDS
      CCDS55228.2
      UniProtKB/TrEMBL
      A0A499FJS7, B4DP95
      Related
      ENSP00000430868.2, ENST00000520835.7
      Conserved Domains (4) summary
      cd17046
      Location:246326
      Ubl_IKKA_like; ubiquitin-like (Ubl) domain found in inhibitor of nuclear factor kappa-B kinases, IKK-alpha and IKK-beta, and similar proteins
      pfam12179
      Location:642678
      IKKbetaNEMObind; I-kappa-kinase-beta NEMO binding domain
      pfam18397
      Location:325599
      IKBKB_SDD; IQBAL scaffold dimerization domain
      cl21453
      Location:1245
      PKc_like; Protein Kinases, catalytic domain
    2. NM_001242778.2NP_001229707.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform 5

      See identical proteins and their annotated locations for NP_001229707.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (7) lacks an alternate exon in the 5' coding region and uses an alternate start codon, compared to variant 1. The resulting isoform (5) has a shorter and distinct N-terminus, compared to variant 1.
      Source sequence(s)
      AC083973, AI379342, AK303528, DA159382
      UniProtKB/TrEMBL
      B4DP95
      Conserved Domains (3) summary
      smart00220
      Location:8231
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      pfam12179
      Location:649683
      IKKbetaNEMObind; I-kappa-kinase-beta NEMO binding domain
      cl21453
      Location:8250
      PKc_like; Protein Kinases, catalytic domain
    3. NM_001556.3NP_001547.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform 1

      See identical proteins and their annotated locations for NP_001547.1

      Status: REVIEWED

      Description
      Transcript Variant: This variant (1) encodes the longest isoform (1).
      Source sequence(s)
      AF080158, AI379342, BC090865, DA709000
      Consensus CDS
      CCDS6128.1
      UniProtKB/Swiss-Prot
      B4DZ30, B4E0U4, O14920, O75327
      UniProtKB/TrEMBL
      B4DP95
      Related
      ENSP00000430684.1, ENST00000520810.6
      Conserved Domains (4) summary
      cd14038
      Location:20309
      STKc_IKK_beta; Catalytic domain of the Serine/Threonine kinase, Inhibitor of Nuclear Factor-KappaB Kinase (IKK) beta
      cd17046
      Location:310390
      Ubl_IKKA_like; ubiquitin-like (Ubl) domain found in inhibitor of nuclear factor kappa-B kinases, IKK-alpha and IKK-beta, and similar proteins
      pfam12179
      Location:708742
      IKKbetaNEMObind; I-kappa-kinase-beta NEMO binding domain
      pfam18397
      Location:389663
      IKBKB_SDD; IQBAL scaffold dimerization domain

    RNA

    1. NR_033818.2 RNA Sequence

      Status: REVIEWED

      Description
      Transcript Variant: This variant (5) has an additional segment in the CDS, resulting in reading frame-shift and earlier translation termination, as compared to variant 1. The transcript is a nonsense-mediated mRNA decay candidate.
      Source sequence(s)
      AC083973, AI379342, BC090865, DA159382
      Related
      ENST00000342222.6
    2. NR_033819.2 RNA Sequence

      Status: REVIEWED

      Description
      Transcript Variant: This variant (6) lacks an exon in the 3' CDS, resulting in reading frame-shift and earlier translation termination, as compared to variant 1. The transcript is a nonsense-mediated mRNA decay candidate.
      Source sequence(s)
      AC083973, AI379342, AK290952, BC108694, DA105584
      Related
      ENST00000416505.7
    3. NR_040009.2 RNA Sequence

      Status: REVIEWED

      Description
      Transcript Variant: This variant (8) uses an alternate splice site, compared to variant 1. This variant is represented as non-coding because the use of the 5'-most expected translational start codon, as used in variant 1, renders the transcript a candidate for nonsense-mediated mRNA decay (NMD).
      Source sequence(s)
      AC083973, AI379342, BC144080, DA159382

    RefSeqs of Annotated Genomes: GCF_000001405.40-RS_2023_10

    The following sections contain reference sequences that belong to a specific genome build. Explain

    Reference GRCh38.p14 Primary Assembly

    Genomic

    1. NC_000008.11 Reference GRCh38.p14 Primary Assembly

      Range
      42271302..42332460
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_047421762.1XP_047277718.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X8

    2. XM_011544520.3XP_011542822.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X5

      UniProtKB/TrEMBL
      B4DP95
      Conserved Domains (4) summary
      smart00220
      Location:38205
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      pfam12179
      Location:623650
      IKKbetaNEMObind; I-kappa-kinase-beta NEMO binding domain
      pfam13900
      Location:700720
      GVQW; Putative domain of unknown function
      cl21453
      Location:45224
      PKc_like; Protein Kinases, catalytic domain
    3. XM_011544517.3XP_011542819.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1

      See identical proteins and their annotated locations for XP_011542819.1

      Conserved Domains (3) summary
      smart00220
      Location:15290
      S_TKc; Serine/Threonine protein kinases, catalytic domain
      cd14038
      Location:20309
      STKc_IKK_beta; Catalytic domain of the Serine/Threonine kinase, Inhibitor of Nuclear Factor-KappaB Kinase (IKK) beta
      pfam13900
      Location:785805
      GVQW; Putative domain of unknown function
    4. XM_047421758.1XP_047277714.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X3

    5. XM_047421764.1XP_047277720.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X10

      UniProtKB/TrEMBL
      G3V105
      Related
      ENSP00000428186.1, ENST00000521661.5
    6. XM_047421757.1XP_047277713.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X2

      UniProtKB/Swiss-Prot
      B4DZ30, B4E0U4, O14920, O75327
    7. XM_047421760.1XP_047277716.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X6

    8. XM_047421761.1XP_047277717.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X7

    9. XM_047421759.1XP_047277715.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X4

    10. XM_047421763.1XP_047277719.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X9

    Alternate T2T-CHM13v2.0

    Genomic

    1. NC_060932.1 Alternate T2T-CHM13v2.0

      Range
      42545654..42606501
      Download
      GenBank, FASTA, Sequence Viewer (Graphics)

    mRNA and Protein(s)

    1. XM_054360434.1XP_054216409.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X8

    2. XM_054360431.1XP_054216406.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X5

    3. XM_054360429.1XP_054216404.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X3

    4. XM_054360427.1XP_054216402.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X1

    5. XM_054360436.1XP_054216411.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X10

      UniProtKB/TrEMBL
      G3V105
    6. XM_054360428.1XP_054216403.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X2

      UniProtKB/Swiss-Prot
      B4DZ30, B4E0U4, O14920, O75327
    7. XM_054360432.1XP_054216407.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X6

    8. XM_054360433.1XP_054216408.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X7

    9. XM_054360430.1XP_054216405.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X4

    10. XM_054360435.1XP_054216410.1  inhibitor of nuclear factor kappa-B kinase subunit beta isoform X9

    Suppressed Reference Sequence(s)

    The following Reference Sequences have been suppressed. Explain

    1. NM_001190721.1: Suppressed sequence

      Description
      NM_001190721.1: This RefSeq was permanently suppressed because currently there is not sufficient data to support this transcript.
    2. NM_001190722.1: Suppressed sequence

      Description
      NM_001190722.1: This RefSeq was permanently suppressed because there is not sufficient data to support this transcript.