VCV000166769.38 - ClinVar

NM_000719.7(CACNA1C):c.3049-10C>T

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.

(10)

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.

Conflicting classifications of pathogenicity
Uncertain significance(1); Benign(4); Likely benign(2)

criteria provided, conflicting classifications

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_000719.7(CACNA1C):c.3049-10C>T

Variation ID: 166769 Accession: VCV000166769.38

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 12p13.33 12: 2605669 (GRCh38) [ NCBI UCSC ] 12: 2714835 (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	Dec 6, 2016	Oct 20, 2024	Jan 31, 2024

HGVS

Nucleotide	Protein	Molecular consequence
NM_000719.7:c.3049-10C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001167623.2:c.3049-10C>T MANE Plus Clinical Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.		intron variant
NM_001129827.2:c.3109-10C>T		intron variant
NM_001129829.2:c.3049-10C>T		intron variant
NM_001129830.3:c.3049-10C>T		intron variant
NM_001129831.2:c.3049-10C>T		intron variant
NM_001129832.2:c.3109-10C>T		intron variant
NM_001129833.2:c.3049-10C>T		intron variant
NM_001129834.2:c.3049-10C>T		intron variant
NM_001129835.2:c.3049-10C>T		intron variant
NM_001129836.2:c.3049-10C>T		intron variant
NM_001129837.2:c.3049-10C>T		intron variant
NM_001129838.2:c.3049-10C>T		intron variant
NM_001129839.2:c.3049-10C>T		intron variant
NM_001129840.2:c.3049-10C>T		intron variant
NM_001129841.2:c.3049-10C>T		intron variant
NM_001129842.2:c.3049-10C>T		intron variant
NM_001129843.2:c.3049-10C>T		intron variant
NM_001129844.2:c.3040-10C>T		intron variant
NM_001129846.2:c.3049-10C>T		intron variant
NM_001167624.3:c.3049-10C>T		intron variant
NM_001167625.2:c.3049-10C>T		intron variant
NM_199460.4:c.3109-10C>T		intron variant
NC_000012.12:g.2605669C>T
NC_000012.11:g.2714835C>T
NG_008801.2:g.639884C>T
LRG_334:g.639884C>T
LRG_334t1:c.3049-10C>T

... more HGVS ... less HGVS

Protein change

Other names

Canonical SPDI

NC_000012.12:2605668:C:T

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.

0.00120 (T)

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

NHLBI Exome Sequencing Project (ESP) Exome Variant Server 0.00077

The Genome Aggregation Database (gnomAD) 0.00093

1000 Genomes Project 30x 0.00094

Trans-Omics for Precision Medicine (TOPMed) 0.00112

Exome Aggregation Consortium (ExAC) 0.00117

The Genome Aggregation Database (gnomAD), exomes 0.00118

1000 Genomes Project 0.00120

Links

ClinGen: CA233581 dbSNP: rs186741807 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.
CACNA1C		Little evidence for dosage pathogenicity	No evidence available	GRCh38 GRCh38 GRCh37	2116	3091

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.
not provided	Conflicting interpretations of pathogenicity (5)	criteria provided, conflicting classifications	May 1, 2023	RCV000587094.34
Congestive heart failure	Likely benign (1)	criteria provided, single submitter	Apr 9, 2019	RCV000852663.10
not specified	Benign (2)	no assertion criteria provided	-	RCV001706014.12
Long QT syndrome	Benign (1)	criteria provided, single submitter	Jan 31, 2024	RCV001081172.17
CACNA1C-related disorder	Benign (1)	no assertion criteria provided	Jul 23, 2019	RCV003917489.2

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 (Mar 06, 2020)	criteria provided, single submitter (ARUP Molecular Germline Variant Investigation Process) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories Accession: SCV001472528.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021
Likely benign (May 01, 2023)	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: SCV004132341.10 First in ClinVar: Nov 20, 2023 Last updated: Oct 20, 2024	Comment: CACNA1C: BS1 Number of individuals with the variant: 3
Benign (Jul 03, 2017)	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: SCV000697547.1 First in ClinVar: Mar 17, 2018 Last updated: Mar 17, 2018	Comment: Variant summary: c.3049-10>T in CACNA1C gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not … (more) Variant summary: c.3049-10>T in CACNA1C gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.001174 (142/120926 chrs tested), including 1 homozygote. The observed frequency exceeds the maximum expected allele frequency for a pathogenic variant of 0.00001, suggesting that it is a common polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but is cited as Likely Benign/Benign by reputable databases/clinical laboratory. Taking together the variant was classified as Benign. (less)
Uncertain significance (Nov 03, 2014)	criteria provided, single submitter (EGL Classification Definitions 2015) Method: clinical testing	not provided Affected status: unknown Allele origin: germline	Eurofins Ntd Llc (ga) Accession: SCV000202327.7 First in ClinVar: Feb 02, 2015 Last updated: Dec 15, 2018	Other databases http://www.egl-eurofins.com/emvc… http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CACNA1C http://www.ncbi.nlm.nih.gov/vari… http://www.ncbi.nlm.nih.gov/variation/tools/1000genomes/?chr=12&from=2714835&to=2714835 Number of individuals with the variant: 3 Sex: mixed
Likely benign (Apr 09, 2019)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	Congestive heart failure Affected status: yes Allele origin: germline	Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego Accession: SCV000995369.1 First in ClinVar: Oct 12, 2019 Last updated: Oct 12, 2019	Number of individuals with the variant: 1
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: SCV001939296.2 First in ClinVar: Sep 29, 2021 Last updated: Mar 04, 2023
Benign (Jan 31, 2024)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Long QT syndrome Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV000562920.9 First in ClinVar: Apr 17, 2017 Last updated: Feb 20, 2024
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Clinical Genetics, Academic Medical Center Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001917057.1 First in ClinVar: Sep 26, 2021 Last updated: Sep 26, 2021
Benign (Jul 23, 2019)	no assertion criteria provided Method: clinical testing	CACNA1C-related condition Affected status: unknown Allele origin: germline	PreventionGenetics, part of Exact Sciences Accession: SCV004728899.2 First in ClinVar: Mar 16, 2024 Last updated: Oct 08, 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).
Benign (-)	no assertion criteria provided Method: clinical testing	not specified Affected status: yes Allele origin: germline	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ Additional submitter: Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen Study: VKGL Data-share Consensus Accession: SCV001955090.1 First in ClinVar: Oct 02, 2021 Last updated: Oct 02, 2021

Comment:

Variant summary: c.3049-10>T in CACNA1C gene is an intronic change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect a normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.001174 (142/120926 chrs tested), including 1 homozygote. The observed frequency exceeds the maximum expected allele frequency for a pathogenic variant of 0.00001, suggesting that it is a common polymorphism. The variant of interest has not, to our knowledge, been reported in affected individuals in published reports but is cited as Likely Benign/Benign by reputable databases/clinical laboratory. Taking together the variant was classified as Benign.

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

Title	Author	Journal	Year	Link
http://www.egl-eurofins.com/emvclass/emvclass.php?approved_symbol=CACNA1C	-	-	-	-

Text-mined citations for rs186741807 ...

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 Nov 10, 2024

ClinVar Genomic variation as it relates to human health

NM_000719.7(CACNA1C):c.3049-10C>T

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs186741807 ...