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CLCN2 chloride voltage-gated channel 2 [ Homo sapiens (human) ]

Gene ID: 1181, updated on 11-Apr-2024

Summary

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Official Symbol
CLCN2provided by HGNC
Official Full Name
chloride voltage-gated channel 2provided by HGNC
Primary source
HGNC:HGNC:2020
See related
Ensembl:ENSG00000114859 MIM:600570; AllianceGenome:HGNC:2020
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
CLC2; ECA2; ECA3; EGI3; EGMA; EJM6; EJM8; FHA2; FHII; CIC-2; EGI11; HALD2; LKPAT; clC-2
Summary
This gene encodes a voltage-gated chloride channel. The encoded protein is a transmembrane protein that maintains chloride ion homeostasis in various cells. Defects in this gene may be a cause of certain epilepsies. Four transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2012]
Expression
Broad expression in testis (RPKM 8.7), colon (RPKM 7.2) and 24 other tissues See more
Orthologs
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Genomic context

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Location:
3q27.1
Exon count:
25
Annotation release Status Assembly Chr Location
RS_2023_10 current GRCh38.p14 (GCF_000001405.40) 3 NC_000003.12 (184346185..184361605, complement)
RS_2023_10 current T2T-CHM13v2.0 (GCF_009914755.1) 3 NC_060927.1 (187155451..187170873, complement)
105.20220307 previous assembly GRCh37.p13 (GCF_000001405.25) 3 NC_000003.11 (184063973..184079393, complement)

Chromosome 3 - NC_000003.12Genomic Context describing neighboring genes Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14959 Neighboring gene proteasome 26S subunit ubiquitin receptor, non-ATPase 2 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:184031817-184032317 Neighboring gene H3K27ac hESC enhancer GRCh37_chr3:184033042-184033663 Neighboring gene eukaryotic translation initiation factor 4 gamma 1 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:184045141-184045641 Neighboring gene small nucleolar RNA, C/D box 66 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20908 Neighboring gene ReSE screen-validated silencer GRCh37_chr3:184053938-184054138 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:184055930-184056541 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20909 Neighboring gene family with sequence similarity 131 member A Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:184061884-184062636 Neighboring gene H3K27ac-H3K4me1 hESC enhancer GRCh37_chr3:184062637-184063388 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:184063389-184064141 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:184064142-184064893 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:184077025-184077538 Neighboring gene H3K4me1 hESC enhancer GRCh37_chr3:184077539-184078050 Neighboring gene uncharacterized LOC124906311 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14964 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14965 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14966 Neighboring gene ATAC-STARR-seq lymphoblastoid silent region 14967 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20910 Neighboring gene ATAC-STARR-seq lymphoblastoid active region 20911 Neighboring gene RNA polymerase II, I and III subunit H Neighboring gene thrombopoietin

Genomic regions, transcripts, and products

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Go to nucleotide: Graphics FASTA GenBank

Expression

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  • 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

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Related articles in PubMed

  1. Biallelic CLCN2 mutations cause retinal degeneration by impairing retinal pigment epithelium phagocytosis and chloride channel function. Xu P, et al. Hum Genet, 2023 Apr. PMID 36964785
  2. Can Unlikely Neanderthal Chloride Channel CLC-2 Gene Variants Provide Insights in Modern Human Infertility? Jeworutzki E, et al. Cell Physiol Biochem, 2021 Jun 19. PMID 34148308
  3. Functional Analysis and Clinical Significance of Chloride Channel 2 Expression in Esophageal Squamous Cell Carcinoma. Mitsuda M, et al. Ann Surg Oncol, 2021 Sep. PMID 33565032
  4. A Novel Loss-of-Function Variant in the Chloride Ion Channel Gene Clcn2 Associates with Atrial Fibrillation. Hansen TH, et al. Sci Rep, 2020 Jan 29. PMID 31996765, Free PMC Article
  5. ClC-2 knockdown prevents cerebrovascular remodeling via inhibition of the Wnt/β-catenin signaling pathway. Lu J, et al. Cell Mol Biol Lett, 2018. PMID 29988306, Free PMC Article

See all (65) citations in PubMed

GeneRIFs: Gene References Into Functions

What's a GeneRIF?
  1. Biallelic CLCN2 mutations cause retinal degeneration by impairing retinal pigment epithelium phagocytosis and chloride channel function.
    Title: Biallelic CLCN2 mutations cause retinal degeneration by impairing retinal pigment epithelium phagocytosis and chloride channel function.
  2. FHII is linked to the chromosome 7p22 region but also shows predicted heterogeneity.
    Title: Familial hyperaldosteronism type II is linked to the chromosome 7p22 region but also shows predicted heterogeneity.
  3. Functional Analysis and Clinical Significance of Chloride Channel 2 Expression in Esophageal Squamous Cell Carcinoma.
    Title: Functional Analysis and Clinical Significance of Chloride Channel 2 Expression in Esophageal Squamous Cell Carcinoma.
  4. Can Unlikely Neanderthal Chloride Channel CLC-2 Gene Variants Provide Insights in Modern Human Infertility?
    Title: Can Unlikely Neanderthal Chloride Channel CLC-2 Gene Variants Provide Insights in Modern Human Infertility?
  5. Regulation of ClC-2 Chloride Channel Proteostasis by Molecular Chaperones: Correction of Leukodystrophy-Associated Defect.
    Title: Regulation of ClC-2 Chloride Channel Proteostasis by Molecular Chaperones: Correction of Leukodystrophy-Associated Defect.
  6. CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy.
    Title: CUL4-DDB1-CRBN E3 Ubiquitin Ligase Regulates Proteostasis of ClC-2 Chloride Channels: Implication for Aldosteronism and Leukodystrophy.
  7. this study shows possible link between loss of ClC-2 function and an increased risk of developing atrial fibrillation
    Title: A Novel Loss-of-Function Variant in the Chloride Ion Channel Gene Clcn2 Associates with Atrial Fibrillation.
  8. Three de novo epilepsy-related gene missense mutations were identified in SCN1A, SCN8A and CLCN2 in childhood absence epilepsy patients.
    Title: De novo SCN1A, SCN8A, and CLCN2 mutations in childhood absence epilepsy.
  9. CLCN2 mutations cause primary aldosteronism, this highlight the importance of chloride in aldosterone biosynthesis and CLCN2 as the foremost chloride conductor of resting glomerulosa cells.
    Title: A gain-of-function mutation in the CLCN2 chloride channel gene causes primary aldosteronism.
  10. A role of anion channels in glomerulosa membrane potential determination, aldosterone production and hypertension. The mutations are the cause of a substantial fraction of early-onset primary aldosteronism.
    Title: CLCN2 chloride channel mutations in familial hyperaldosteronism type II.
Submit: New GeneRIF Correction See all GeneRIFs (50)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Genotypes

Interactions

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Products Interactant Other Gene Complex Source Pubs Description

General gene information

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Markers

Homology

Gene Ontology Provided by GOA

Function Evidence Code Pubs
enables voltage-gated chloride channel activity IBA
Inferred from Biological aspect of Ancestor
more info
  
enables voltage-gated chloride channel activity IDA
Inferred from Direct Assay
more info
 PubMed 
Process Evidence Code Pubs
involved_in acinar cell differentiation IEA
Inferred from Electronic Annotation
more info
  
involved_in cell differentiation involved in salivary gland development IEA
Inferred from Electronic Annotation
more info
  
involved_in chloride transmembrane transport IEA
Inferred from Electronic Annotation
more info
  
involved_in chloride transport IBA
Inferred from Biological aspect of Ancestor
more info
  
involved_in lung development IEA
Inferred from Electronic Annotation
more info
  
involved_in positive regulation of oligodendrocyte differentiation IEA
Inferred from Electronic Annotation
more info
  
involved_in regulation of aldosterone biosynthetic process IMP
Inferred from Mutant Phenotype
more info
 PubMed 
involved_in retina development in camera-type eye IEA
Inferred from Electronic Annotation
more info
  
Component Evidence Code Pubs
part_of chloride channel complex IEA
Inferred from Electronic Annotation
more info
  
located_in dendrite IEA
Inferred from Electronic Annotation
more info
  
located_in perikaryon IEA
Inferred from Electronic Annotation
more info
  
is_active_in plasma membrane IBA
Inferred from Biological aspect of Ancestor
more info
  
located_in plasma membrane IDA
Inferred from Direct Assay
more info
 PubMed 
located_in plasma membrane TAS
Traceable Author Statement
more info
  

General protein information

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Preferred Names
chloride channel protein 2
Names
chloride channel 2
chloride channel, voltage-sensitive 2

NCBI Reference Sequences (RefSeq)

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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_016422.1 RefSeqGene

    Range
    4999..20419
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. NM_001171087.3 → NP_001164558.1  chloride channel protein 2 isoform 2

    See identical proteins and their annotated locations for NP_001164558.1

    Status: REVIEWED

    Description
    Transcript Variant: This variant (2) uses an alternate in-frame splice junction at the 5' end of an exon compared to variant 1. The resulting isoform (2) has the same N- and C-termini but is shorter compared to isoform 1.
    Source sequence(s)
    AA524434, BC072004, DC403930
    Consensus CDS
    CCDS54691.1
    UniProtKB/Swiss-Prot
    P51788
    Related
    ENSP00000345056.7, ENST00000344937.11
    Conserved Domains (3) summary
    cd03683
    Location:90 → 550
    ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...
    cd04591
    Location:773 → 821
    CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...
    pfam00654
    Location:143 → 529
    Voltage_CLC; Voltage gated chloride channel

  2. NM_001171088.3 → NP_001164559.1  chloride channel protein 2 isoform 3

    Status: REVIEWED

    Description
    Transcript Variant: This variant (3) lacks an alternate in-frame exon compared to variant 1. The resulting isoform (3) has the same N- and C-termini but is shorter compared to isoform 1.
    Source sequence(s)
    AA524434, AC078797, AK302759, DC403930
    Consensus CDS
    CCDS54690.1
    UniProtKB/Swiss-Prot
    P51788
    Related
    ENSP00000400425.2, ENST00000434054.6
    Conserved Domains (3) summary
    cd03683
    Location:73 → 523
    ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...
    cd04591
    Location:746 → 794
    CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...
    pfam00654
    Location:99 → 502
    Voltage_CLC; Voltage gated chloride channel

  3. NM_001171089.3 → NP_001164560.1  chloride channel protein 2 isoform 4

    Status: REVIEWED

    Description
    Transcript Variant: This variant (4) lacks an alternate in-frame exon compared to variant 1. The resulting isoform (4) has the same N- and C-termini but is shorter compared to isoform 1.
    Source sequence(s)
    AA524434, AC078797, AK298952, DC403930
    Consensus CDS
    CCDS54692.1
    UniProtKB/Swiss-Prot
    P51788
    Related
    ENSP00000391928.1, ENST00000457512.1
    Conserved Domains (2) summary
    cd03683
    Location:90 → 567
    ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...
    pfam00654
    Location:143 → 546
    Voltage_CLC; Voltage gated chloride channel

  4. NM_004366.6 → NP_004357.3  chloride channel protein 2 isoform 1

    See identical proteins and their annotated locations for NP_004357.3

    Status: REVIEWED

    Description
    Transcript Variant: This variant (1) represents the longest transcript and encodes the longest isoform (1).
    Source sequence(s)
    AA524434, AC078797, AF026004, DC403930
    Consensus CDS
    CCDS3263.1
    UniProtKB/Swiss-Prot
    B4DQT9, B4DZ58, E9PBD9, E9PCD2, O14864, P51788, Q6IPA9, Q8WU13
    Related
    ENSP00000265593.4, ENST00000265593.9
    Conserved Domains (3) summary
    cd03683
    Location:90 → 567
    ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...
    cd04591
    Location:790 → 838
    CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...
    pfam00654
    Location:143 → 546
    Voltage_CLC; Voltage gated chloride channel

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_000003.12 Reference GRCh38.p14 Primary Assembly

    Range
    184346185..184361605 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_006713489.2 → XP_006713552.1  chloride channel protein 2 isoform X1

    See identical proteins and their annotated locations for XP_006713552.1

    Conserved Domains (3) summary
    cd03683
    Location:90 → 567
    ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...
    cd04591
    Location:762 → 803
    CBS_pair_EriC_assoc_euk_bac; This cd contains two tandem repeats of the cystathionine beta-synthase (CBS pair) domains in the EriC CIC-type chloride channels in eukaryotes and bacteria. These ion channels are proteins with a seemingly simple task of allowing the passive flow of ...
    pfam00654
    Location:143 → 546
    Voltage_CLC; Voltage gated chloride channel

  2. XM_011512401.2 → XP_011510703.1  chloride channel protein 2 isoform X2

    Conserved Domains (2) summary
    cd03683
    Location:90 → 567
    ClC_1_like; ClC-1-like chloride channel proteins. This CD includes isoforms ClC-0, ClC-1, ClC-2 and ClC_K. ClC-1 is expressed in skeletal muscle and its mutation leads to both recessively and dominantly-inherited forms of muscle stiffness or myotonia. ClC-K is ...
    pfam00654
    Location:143 → 546
    Voltage_CLC; Voltage gated chloride channel

  3. XM_047447419.1 → XP_047303375.1  chloride channel protein 2 isoform X3

    Related
    ENSP00000490313.1, ENST00000636492.1

Alternate T2T-CHM13v2.0

Genomic

  1. NC_060927.1 Alternate T2T-CHM13v2.0

    Range
    187155451..187170873 complement
    Download
    GenBank, FASTA, Sequence Viewer (Graphics)

mRNA and Protein(s)

  1. XM_054345165.1 → XP_054201140.1  chloride channel protein 2 isoform X1

  2. XM_054345166.1 → XP_054201141.1  chloride channel protein 2 isoform X2

  3. XM_054345167.1 → XP_054201142.1  chloride channel protein 2 isoform X3

Nucleotide Protein
Heading Accession and Version
Protein Accession Links
GenPept Link UniProtKB Link
P51788.2 GenPept UniProtKB/Swiss-Prot:P51788

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