VCV000242263.35 - ClinVar

NM_201596.3(CACNB2):c.993G>A (p.Ser331=)

Germline

Classification

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.

(7)

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.

Benign

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_201596.3(CACNB2):c.993G>A (p.Ser331=)

Variation ID: 242263 Accession: VCV000242263.35

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 10p12.31 10: 18527636 (GRCh38) [ NCBI UCSC ] 10: 18816565 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	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	Oct 2, 2016	Oct 20, 2024	May 1, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_201596.3:c.993G>A MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_963890.2:p.Ser331=	synonymous
NM_201590.3:c.831G>A MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_963884.2:p.Ser277=	synonymous
NM_000724.4:c.828G>A	NP_000715.2:p.Ser276=	synonymous
NM_001167945.2:c.795G>A	NP_001161417.1:p.Ser265=	synonymous
NM_001330060.2:c.714G>A	NP_001316989.1:p.Ser238=	synonymous
NM_201570.3:c.849G>A	NP_963864.1:p.Ser283=	synonymous
NM_201571.4:c.909G>A	NP_963865.2:p.Ser303=	synonymous
NM_201572.4:c.837G>A	NP_963866.2:p.Ser279=	synonymous
NM_201593.3:c.879G>A	NP_963887.2:p.Ser293=	synonymous
NM_201597.3:c.921G>A	NP_963891.1:p.Ser307=	synonymous
NC_000010.11:g.18527636G>A
NC_000010.10:g.18816565G>A
NG_016195.1:g.391960G>A
LRG_381:g.391960G>A
LRG_381t1:c.993G>A	LRG_381p1:p.Ser331=
LRG_381t2:c.831G>A	LRG_381p2:p.Ser277=

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000010.11:18527635:G:A

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

Global minor allele frequency (GMAF) Help The 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.

0.00359 (A)

Allele frequency Help The frequency of the allele represented by this VCV record.

1000 Genomes Project 30x 0.00344

1000 Genomes Project 0.00359

The Genome Aggregation Database (gnomAD), exomes 0.00725

Exome Aggregation Consortium (ExAC) 0.00729

Trans-Omics for Precision Medicine (TOPMed) 0.00842

The Genome Aggregation Database (gnomAD) 0.00852

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00961

Links

ClinGen: CA5429866 dbSNP: rs76956014 VarSome

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
Gene	OMIM	HI score Help 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.
CACNB2		-	-	GRCh38 GRCh37	939	967

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.
Cardiovascular phenotype	Benign (1)	criteria provided, single submitter	Aug 27, 2015	RCV000249791.3
not provided	Benign (4)	criteria provided, multiple submitters, no conflicts	May 1, 2024	RCV000589174.15
Brugada syndrome 4	Benign (2)	criteria provided, multiple submitters, no conflicts	Jan 31, 2024	RCV001000333.19

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.
Benign (Aug 09, 2016)	criteria provided, single submitter (LabCorp Variant Classification Summary - May 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Women's Health and Genetics/Laboratory Corporation of America, LabCorp Accession: SCV000700050.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Comment: Variant summary: The CACNB2 c.831G>A (p.Ser277Ser) variant causes a synonymous change involving a non-conserved nucleotide. 5/5 splice prediction tools predict no significant impact on normal … (more) Variant summary: The CACNB2 c.831G>A (p.Ser277Ser) variant causes a synonymous change involving a non-conserved nucleotide. 5/5 splice prediction tools predict no significant impact on normal splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 884/121214 (1/137, 9 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic CACNB2 variant of 1/100000 (0.00001), suggesting this variant is likely a benign polymorphism. A reputable clinical laboratory cites the variant as "benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign. (less)
Benign (Mar 03, 2015)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV001899829.1 First in ClinVar: Sep 23, 2021 Last updated: Sep 23, 2021
Benign (Nov 01, 2023)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process 2024) Method: clinical testing	Brugada syndrome 4 Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001157058.5 First in ClinVar: Feb 10, 2020 Last updated: Feb 20, 2024
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Brugada syndrome 4 Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000291911.10 First in ClinVar: Jul 01, 2016 Last updated: Feb 28, 2024
Benign (Aug 27, 2015)	criteria provided, single submitter (Ambry Variant Classification Scheme 2023) Method: clinical testing	Cardiovascular phenotype Affected status: unknown Allele origin: germline	Ambry Genetics Accession: SCV000318132.7 First in ClinVar: Oct 02, 2016 Last updated: May 01, 2024	Comment: This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation … (more) This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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)
Benign (-)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: not provided	not provided (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Breakthrough Genomics, Breakthrough Genomics Accession: SCV005320477.1 First in ClinVar: Sep 29, 2024 Last updated: Sep 29, 2024
Benign (May 01, 2024)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV004126522.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: CACNB2: BP4, BP7, BS1, BS2 Number of individuals with the variant: 3

Comment:

Variant summary: The CACNB2 c.831G>A (p.Ser277Ser) variant causes a synonymous change involving a non-conserved nucleotide. 5/5 splice prediction tools predict no significant impact on normal splicing. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 884/121214 (1/137, 9 homozygotes), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic CACNB2 variant of 1/100000 (0.00001), suggesting this variant is likely a benign polymorphism. A reputable clinical laboratory cites the variant as "benign." Therefore, taking all available lines of evidence into consideration, the variant of interest has been classified as Benign.

Comment:

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, 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.

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.

Comment:

Citations for germline classification of this variant

There are no citations for germline classification of this variant in ClinVar. If you know of citations for this variation, please consider submitting that information to ClinVar.

Text-mined citations for rs76956014 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_201596.3(CACNB2):c.993G>A (p.Ser331=)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs76956014 ...