rs199473660

Positions:

• chr12-2688702-G-A
• chr12-2688702-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_000719.7(CACNA1C):​c.6040G>A​(p.Val2014Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000249 in 1,610,992 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:3 O:1
• Conservation: PhyloP100: 4.98

Genes affected

CACNA1C (HGNC:1390): (calcium voltage-gated channel subunit alpha1 C) This gene encodes an alpha-1 subunit of a voltage-dependent calcium channel. Calcium channels mediate the influx of calcium ions into the cell upon membrane polarization. The alpha-1 subunit consists of 24 transmembrane segments and forms the pore through which ions pass into the cell. The calcium channel consists of a complex of alpha-1, alpha-2/delta, beta, and gamma subunits in a 1:1:1:1 ratio. There are multiple isoforms of each of these proteins, either encoded by different genes or the result of alternative splicing of transcripts. The protein encoded by this gene binds to and is inhibited by dihydropyridine. Alternative splicing results in many transcript variants encoding different proteins. Some of the predicted proteins may not produce functional ion channel subunits. [provided by RefSeq, Oct 2012]

CACNA1C (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.
• BP4: Computational evidence support a benign effect (MetaRNN=0.046481907).
• BP6: Variant 12-2688702-G-A is Benign according to our data. Variant chr12-2688702-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 67556.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=6, not_provided=1, Benign=1}. Variant chr12-2688702-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000184 (28/152282) while in subpopulation SAS AF= 0.00124 (6/4830). AF 95% confidence interval is 0.000541. There are 0 homozygotes in gnomad4. There are 16 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 28 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.6040G>A	p.Val2014Ile	missense_variant	46/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.6040G>A	p.Val2014Ile	missense_variant	46/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.6040G>A	p.Val2014Ile	missense_variant	46/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.6040G>A	p.Val2014Ile	missense_variant	46/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6379G>A	p.Val2127Ile	missense_variant	49/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6253G>A	p.Val2085Ile	missense_variant	47/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6220G>A	p.Val2074Ile	missense_variant	46/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6205G>A	p.Val2069Ile	missense_variant	47/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6184G>A	p.Val2062Ile	missense_variant	48/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6163G>A	p.Val2055Ile	missense_variant	46/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6145G>A	p.Val2049Ile	missense_variant	47/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6145G>A	p.Val2049Ile	missense_variant	47/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6130G>A	p.Val2044Ile	missense_variant	46/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6130G>A	p.Val2044Ile	missense_variant	46/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6130G>A	p.Val2044Ile	missense_variant	46/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6130G>A	p.Val2044Ile	missense_variant	46/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6124G>A	p.Val2042Ile	missense_variant	47/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.6115G>A	p.Val2039Ile	missense_variant	47/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.6100G>A	p.Val2034Ile	missense_variant	47/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.6097G>A	p.Val2033Ile	missense_variant	46/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.6097G>A	p.Val2033Ile	missense_variant	46/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.6097G>A	p.Val2033Ile	missense_variant	46/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.6091G>A	p.Val2031Ile	missense_variant	46/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.6082G>A	p.Val2028Ile	missense_variant	46/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.6064G>A	p.Val2022Ile	missense_variant	45/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.6064G>A	p.Val2022Ile	missense_variant	45/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.6058G>A	p.Val2020Ile	missense_variant	45/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.6040G>A	p.Val2014Ile	missense_variant	46/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.6040G>A	p.Val2014Ile	missense_variant	46/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.6040G>A	p.Val2014Ile	missense_variant	46/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.6040G>A	p.Val2014Ile	missense_variant	46/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.6040G>A	p.Val2014Ile	missense_variant	46/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.6031G>A	p.Val2011Ile	missense_variant	46/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.6007G>A	p.Val2003Ile	missense_variant	45/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000184 AC: 28 AN: 152164 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000345 AC: 83 AN: 240516 Hom.: 0 AF XY: 0.000388 AC XY: 51 AN XY: 131376

Gnomad AFR exome AF: 0.000414

Gnomad AMR exome AF: 0.0000586

Gnomad ASJ exome AF: 0.000511

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000825

Gnomad FIN exome AF: 0.000885

Gnomad NFE exome AF: 0.000231

Gnomad OTH exome AF: 0.000339

GnomAD4 exome AF: 0.000256 AC: 373 AN: 1458710 Hom.: 0 Cov.: 33 AF XY: 0.000274 AC XY: 199 AN XY: 725598

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.0000674

Gnomad4 ASJ exome AF: 0.000768

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000825

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.000203

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000184 AC: 28 AN: 152282 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74458

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000387 Hom.: 0

Bravo AF: 0.000193

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000488 AC: 4

ExAC AF: 0.000357 AC: 43

EpiCase AF: 0.000218

EpiControl AF: 0.000238

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 11, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	CACNA1C: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2016	p.Val2014Ile (GTC>ATC): c.6040 G>A in exon 46 in the CACNA1C gene (NM_000719.6). The V2014I variant was not observed with any significant frequency in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The V2014I variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. A recent publication classifies V2014I as a variant of unknown significance (Dorschner et al., 2013). The variant is found in LQT panel(s). -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 11, 2015	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 25, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: 4 papers in HGMD, 3 reference presence in control databases; ExAC: 0.1% (19/13788) South Asian chromosomes -

CACNA1C-related disorder Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 27, 2024

The CACNA1C c.6040G>A variant is predicted to result in the amino acid substitution p.Val2014Ile. This variant was reported in individuals with Brugada syndrome (Table1, Burashnikov et al. 2010. PubMed ID: 20817017; Risgaard et al. 2013. PubMed ID: 23414114). This variant is mainly classified as likely benign/uncertain by multiple publications (Table S1, Dorschner et al. 2013. PubMed ID: 24055113; Amendola et al. 2015. PubMed ID: 25637381; Marschall et al. 2019. PubMed ID: 31737537; Maltese et al. 2019. PubMed ID: 31539150 ) and likely pathogenic by one publication (Campuzano et al. 2019. PubMed ID: 30821013). This variant is reported in 0.082% of alleles in individuals of South Asian descent in gnomAD. In ClinVar, this variant has conflicting interpretations of benign, likely benign, and uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/67556/?new_evidence=true). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Brugada syndrome (shorter-than-normal QT interval) Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Brugada syndrome 3 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Mar 17, 2018

- -

Timothy syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Long QT syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 10, 2022

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. -

Brugada syndrome Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

-

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:20817017). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.058	D
MetaRNN	Benign	0.046	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.85	T
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.68	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.12
Sift	Benign	0.051	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;D;D;D;.
Sift4G	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.53, 0.43, 0.44, 0.18, 0.59, 0.64, 0.76, 0.93, 0.81	.;P;B;B;B;P;P;P;B;P;P;P;P;P;P;.;P;P;.;.;.;P;.
Vest4		0.49
MVP		0.53
MPC		0.17
ClinPred		0.029	T
GERP RS		5.2
gMVP		0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs199473660; hg19: chr12-2797868; COSMIC: COSV59772541; COSMIC: COSV59772541;