rs757629968

Variant names:

• chr12-2677102-G-A
• rs757629968
• NM_000719.7:c.4837G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2677102-G-A
• chr12-2677102-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_000719.7(CACNA1C):​c.4837G>A​(p.Val1613Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,613,180 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.15

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-AS1 (HGNC:):

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.35662267).
• BS2: High AC in GnomAdExome4 at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4837G>A	p.Val1613Ile	missense_variant	Exon 40 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4837G>A	p.Val1613Ile	missense_variant	Exon 40 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4837G>A	p.Val1613Ile	missense_variant	Exon 40 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4837G>A	p.Val1613Ile	missense_variant	Exon 40 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5071G>A	p.Val1691Ile	missense_variant	Exon 42 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4837G>A	p.Val1613Ile	missense_variant	Exon 40 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4804G>A	p.Val1602Ile	missense_variant	Exon 39 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5002G>A	p.Val1668Ile	missense_variant	Exon 41 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4981G>A	p.Val1661Ile	missense_variant	Exon 42 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4960G>A	p.Val1654Ile	missense_variant	Exon 40 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4837G>A	p.Val1613Ile	missense_variant	Exon 40 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4837G>A	p.Val1613Ile	missense_variant	Exon 40 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4927G>A	p.Val1643Ile	missense_variant	Exon 40 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4927G>A	p.Val1643Ile	missense_variant	Exon 40 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4927G>A	p.Val1643Ile	missense_variant	Exon 40 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4927G>A	p.Val1643Ile	missense_variant	Exon 40 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4921G>A	p.Val1641Ile	missense_variant	Exon 41 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4912G>A	p.Val1638Ile	missense_variant	Exon 41 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4897G>A	p.Val1633Ile	missense_variant	Exon 41 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4894G>A	p.Val1632Ile	missense_variant	Exon 40 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4894G>A	p.Val1632Ile	missense_variant	Exon 40 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4894G>A	p.Val1632Ile	missense_variant	Exon 40 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4888G>A	p.Val1630Ile	missense_variant	Exon 40 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4879G>A	p.Val1627Ile	missense_variant	Exon 40 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4861G>A	p.Val1621Ile	missense_variant	Exon 39 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4861G>A	p.Val1621Ile	missense_variant	Exon 39 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4855G>A	p.Val1619Ile	missense_variant	Exon 39 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4837G>A	p.Val1613Ile	missense_variant	Exon 40 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4837G>A	p.Val1613Ile	missense_variant	Exon 40 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4837G>A	p.Val1613Ile	missense_variant	Exon 40 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4837G>A	p.Val1613Ile	missense_variant	Exon 40 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4837G>A	p.Val1613Ile	missense_variant	Exon 40 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4828G>A	p.Val1610Ile	missense_variant	Exon 40 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4804G>A	p.Val1602Ile	missense_variant	Exon 39 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000806 AC: 2 AN: 248004 Hom.: 0 AF XY: 0.00000744 AC XY: 1 AN XY: 134468

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000198 AC: 29 AN: 1460974 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726628

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000386 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.00000826 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Oct 05, 2018

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val1613Ile variant (rs757629968) has not been reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.0008 percent (identified on 2 out of 245,050 chromosomes) and has been reported to the ClinVar database (Variation ID: 456973). The valine at position 1613 is highly conserved and computational analyses of the effects of the p.Val1613Ile variant on protein structure and function provide conflicting results (SIFT: deleterious, PolyPhen-2: benign). Altogether, there is not enough evidence to classify the p.Val1613Ile variant with certainty. -

Long QT syndrome Uncertain:1

Feb 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 1613 of the CACNA1C protein (p.Val1613Ile). This variant is present in population databases (rs757629968, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 456973). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype Uncertain:1

Jul 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.V1613I variant (also known as c.4837G>A), located in coding exon 40 of the CACNA1C gene, results from a G to A substitution at nucleotide position 4837. The valine at codon 1613 is replaced by isoleucine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.36	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.81	.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.91	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.31
Sift	Benign	0.098	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.10	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99, 1.0, 0.30, 0.99, 0.35, 0.40, 0.68, 0.96, 0.31, 0.27, 1.0, 0.36, 0.0090, 0.010	.;D;D;B;D;B;B;P;D;B;B;B;D;B;B;.;B;B;.;.;.;B;.
Vest4		0.40
MutPred		0.60		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at E1660 (P = 0.0044);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.55
MPC		1.7
ClinPred		0.81	D
GERP RS		4.3
gMVP		0.91

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: rs757629968; hg19: chr12-2786268;