ClinVar Genomic variation as it relates to human health
NM_000742.4(CHRNA2):c.1434C>A (p.Asp478Glu)
The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.
Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.
Uncertain significance(1); Benign(6); Likely benign(4)
No data submitted for somatic clinical impact
No data submitted for oncogenicity
Variant Details
- Identifiers
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NM_000742.4(CHRNA2):c.1434C>A (p.Asp478Glu)
Variation ID: 136753 Accession: VCV000136753.62
- Type and length
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single nucleotide variant, 1 bp
- Location
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Cytogenetic: 8p21.2 8: 27463009 (GRCh38) [ NCBI UCSC ] 8: 27320526 (GRCh37) [ NCBI UCSC ]
- Timeline in ClinVar
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First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.
Last submission Help The date of the most recent submission for each type of classification for this variant.
Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline Aug 7, 2015 Apr 15, 2024 Feb 1, 2024 - HGVS
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Nucleotide Protein Molecular
consequenceNM_000742.4:c.1434C>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.
NP_000733.2:p.Asp478Glu missense NM_001282455.2:c.1389C>A NP_001269384.1:p.Asp463Glu missense NM_001347705.2:c.957C>A NP_001334634.1:p.Asp319Glu missense NM_001347706.2:c.957C>A NP_001334635.1:p.Asp319Glu missense NM_001347707.2:c.840C>A NP_001334636.1:p.Asp280Glu missense NM_001347708.2:c.840C>A NP_001334637.1:p.Asp280Glu missense NC_000008.11:g.27463009G>T NC_000008.10:g.27320526G>T NG_015827.1:g.21288C>A - Protein change
- D478E, D319E, D280E, D463E
- Other names
- p.D478E:GAC>GAA
- Canonical SPDI
- NC_000008.11:27463008:G:T
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Functional
consequence HelpThe effect of the variant on RNA or protein function, based on experimental evidence from submitters.
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Global minor allele
frequency (GMAF) HelpThe global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.
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0.00160 (T)
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Allele frequency
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The frequency of the allele represented by this VCV record.
1000 Genomes Project 0.00160
1000 Genomes Project 30x 0.00172
The Genome Aggregation Database (gnomAD), exomes 0.00307
Trans-Omics for Precision Medicine (TOPMed) 0.00330
Exome Aggregation Consortium (ExAC) 0.00338
NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00415
Genes
Gene | OMIM | ClinGen Gene Dosage Sensitivity Curation |
Variation Viewer
Help
Links to Variation Viewer, a genome browser to view variation data from NCBI databases. |
Related variants | ||
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HI score
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The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
TS score
Help
The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team. |
Within gene
Help
The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants. |
All
Help
The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene. |
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CHRNA2 | - | - |
GRCh38 GRCh37 |
732 | 813 |
Conditions - Germline
Condition
Help
The condition for this variant-condition (RCV) record in ClinVar. |
Classification
Help
The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions) |
Review status
Help
The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. |
Last evaluated
Help
The most recent date that a submitter evaluated this variant for the condition. |
Variation/condition record
Help
The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page. |
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Benign/Likely benign (2) |
criteria provided, multiple submitters, no conflicts
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Mar 13, 2017 | RCV000124278.13 | |
Benign/Likely benign (3) |
criteria provided, multiple submitters, no conflicts
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Feb 1, 2024 | RCV000419685.16 | |
Conflicting interpretations of pathogenicity (3) |
criteria provided, conflicting classifications
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Mar 30, 2021 | RCV000768183.16 | |
Benign (1) |
criteria provided, single submitter
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Jan 27, 2024 | RCV001080927.15 | |
Likely benign (1) |
criteria provided, single submitter
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Sep 9, 2018 | RCV002312821.8 | |
Benign (1) |
criteria provided, single submitter
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Apr 12, 2019 | RCV003905194.1 |
Submissions - Germline
Classification
Help
The submitted germline classification for each SCV record. (Last evaluated) |
Review status
Help
Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria) |
Condition
Help
The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant. |
Submitter
Help
The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar. |
More information
Help
This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter. |
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Likely Benign
(Sep 01, 2016)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: not provided
Allele origin:
germline
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Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Accession: SCV000511714.1
First in ClinVar: Mar 08, 2017 Last updated: Mar 08, 2017 |
Comment:
Converted during submission to Likely benign.
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Benign
(May 13, 2013)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: yes
Allele origin:
germline
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GeneDx
Accession: SCV000167705.12
First in ClinVar: Jun 23, 2014 Last updated: Aug 07, 2015 |
Comment:
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at … (more)
This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. (less)
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Benign
(Nov 12, 2018)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: unknown
Allele origin:
germline
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Athena Diagnostics Inc
Accession: SCV001143532.1
First in ClinVar: Jan 18, 2020 Last updated: Jan 18, 2020 |
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Uncertain significance
(Mar 30, 2021)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nocturnal frontal lobe epilepsy 4
Affected status: unknown
Allele origin:
germline
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Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago
Accession: SCV000898604.2
First in ClinVar: Apr 25, 2019 Last updated: May 06, 2023 |
Comment:
CHRNA2 NM_000742 exon 6 p.Asp478Glu (c.1434C>A): This variant has not been reported in the literature but is present in 0.5% (685/126322) of European alleles, including … (more)
CHRNA2 NM_000742 exon 6 p.Asp478Glu (c.1434C>A): This variant has not been reported in the literature but is present in 0.5% (685/126322) of European alleles, including 1 homozygote, in the Genome Aggregation Database (http://gnomad.broadinstitute.org/rs56344740). This variant is present in ClinVar, with several labs classifying this variant as likely benign or benign (Variation ID:136753). Evolutionary conservation and computational predictive tools suggest that this variant may not impact the protein. Functional studies predict that this variant will impact the protein (Dash 2014 PMID:24950454). However, these studies may not accurately represent human biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. (less)
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Benign
(Jan 27, 2024)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nocturnal frontal lobe epilepsy
Affected status: unknown
Allele origin:
germline
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Invitae
Accession: SCV000285613.9
First in ClinVar: Jul 01, 2016 Last updated: Feb 20, 2024 |
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Benign
(Apr 12, 2019)
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criteria provided, single submitter
Method: clinical testing
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CHRNA2-related condition
Affected status: unknown
Allele origin:
germline
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PreventionGenetics, part of Exact Sciences
Accession: SCV004725787.1
First in ClinVar: Mar 16, 2024 Last updated: Mar 16, 2024 |
Comment:
This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
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Likely benign
(Mar 13, 2017)
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criteria provided, single submitter
Method: clinical testing
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not specified
Affected status: unknown
Allele origin:
germline
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Eurofins Ntd Llc (ga)
Accession: SCV000706592.2
First in ClinVar: Aug 07, 2015 Last updated: May 03, 2018 |
Number of individuals with the variant: 1
Sex: mixed
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Benign
(Jan 13, 2018)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nocturnal frontal lobe epilepsy 4
Affected status: unknown
Allele origin:
germline
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Illumina Laboratory Services, Illumina
Accession: SCV000473182.3
First in ClinVar: Dec 06, 2016 Last updated: May 31, 2020 |
Comment:
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated … (more)
This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. (less)
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Likely benign
(Jan 01, 2019)
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criteria provided, single submitter
Method: clinical testing
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Autosomal dominant nocturnal frontal lobe epilepsy 4
Affected status: yes
Allele origin:
unknown
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Institute of Human Genetics, University of Leipzig Medical Center
Accession: SCV001440254.1
First in ClinVar: Oct 31, 2020 Last updated: Oct 31, 2020 |
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Likely benign
(Sep 09, 2018)
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criteria provided, single submitter
Method: clinical testing
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Inborn genetic diseases
Affected status: unknown
Allele origin:
germline
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Ambry Genetics
Accession: SCV000848373.3
First in ClinVar: Nov 08, 2018 Last updated: Nov 29, 2022 |
Comment:
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, … (more)
This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. (less)
Number of individuals with the variant: 1
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Benign
(Feb 01, 2024)
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criteria provided, single submitter
Method: clinical testing
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not provided
Affected status: yes
Allele origin:
germline
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CeGaT Center for Human Genetics Tuebingen
Accession: SCV004164534.4
First in ClinVar: Nov 20, 2023 Last updated: Apr 15, 2024 |
Comment:
CHRNA2: BP4, BS1, BS2
Number of individuals with the variant: 9
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Germline Functional Evidence
There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar. |
Citations for germline classification of this variant
HelpTitle | Author | Journal | Year | Link |
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Two rare variations, D478N and D478E, that occur at the same amino acid residue in nicotinic acetylcholine receptor (nAChR) α2 subunit influence nAChR function. | Dash B | Neuropharmacology | 2014 | PMID: 24950454 |
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CHRNA2 | - | - | - | - |
Text-mined citations for rs56344740 ...
HelpRecord last updated Apr 15, 2024
This date represents the last time this VCV record was updated. The update may be due to an update to one of the included submitted records (SCVs), or due to an update that ClinVar made to the variant such as adding HGVS expressions or a rs number. So this date may be different from the date of the “most recent submission” reported at the top of this page.