rs374528680

Variant names:

• chr12-2686216-G-A
• rs374528680
• NM_000719.7:c.5731G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2686216-G-A
• chr12-2686216-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_000719.7(CACNA1C):​c.5731G>A​(p.Gly1911Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000806 in 1,613,618 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 5.10

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 -3 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.
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5731G>A	p.Gly1911Arg	missense_variant	Exon 45 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5731G>A	p.Gly1911Arg	missense_variant	Exon 45 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5731G>A	p.Gly1911Arg	missense_variant	Exon 45 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5731G>A	p.Gly1911Arg	missense_variant	Exon 45 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6070G>A	p.Gly2024Arg	missense_variant	Exon 48 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5944G>A	p.Gly1982Arg	missense_variant	Exon 46 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5911G>A	p.Gly1971Arg	missense_variant	Exon 45 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5896G>A	p.Gly1966Arg	missense_variant	Exon 46 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5875G>A	p.Gly1959Arg	missense_variant	Exon 47 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5854G>A	p.Gly1952Arg	missense_variant	Exon 45 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5836G>A	p.Gly1946Arg	missense_variant	Exon 46 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5836G>A	p.Gly1946Arg	missense_variant	Exon 46 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5821G>A	p.Gly1941Arg	missense_variant	Exon 45 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5821G>A	p.Gly1941Arg	missense_variant	Exon 45 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5821G>A	p.Gly1941Arg	missense_variant	Exon 45 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5821G>A	p.Gly1941Arg	missense_variant	Exon 45 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5815G>A	p.Gly1939Arg	missense_variant	Exon 46 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5806G>A	p.Gly1936Arg	missense_variant	Exon 46 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5791G>A	p.Gly1931Arg	missense_variant	Exon 46 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5788G>A	p.Gly1930Arg	missense_variant	Exon 45 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5788G>A	p.Gly1930Arg	missense_variant	Exon 45 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5788G>A	p.Gly1930Arg	missense_variant	Exon 45 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5782G>A	p.Gly1928Arg	missense_variant	Exon 45 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5773G>A	p.Gly1925Arg	missense_variant	Exon 45 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5755G>A	p.Gly1919Arg	missense_variant	Exon 44 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5755G>A	p.Gly1919Arg	missense_variant	Exon 44 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5749G>A	p.Gly1917Arg	missense_variant	Exon 44 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5731G>A	p.Gly1911Arg	missense_variant	Exon 45 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5731G>A	p.Gly1911Arg	missense_variant	Exon 45 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5731G>A	p.Gly1911Arg	missense_variant	Exon 45 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5731G>A	p.Gly1911Arg	missense_variant	Exon 45 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5731G>A	p.Gly1911Arg	missense_variant	Exon 45 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5722G>A	p.Gly1908Arg	missense_variant	Exon 45 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5698G>A	p.Gly1900Arg	missense_variant	Exon 44 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152244 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: 0.00000401 AC: 1 AN: 249308 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135252

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461374 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 726982

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000989

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

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

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1911 of the CACNA1C protein (p.Gly1911Arg). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with long QT syndrome or Brugada syndrome (PMID: 25184293, 26230511). This variant is also known as c.5875G>C, p.Gly1959Arg. ClinVar contains an entry for this variant (Variation ID: 842047). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt CACNA1C protein function with a negative predictive value of 95%. Experimental studies have shown that this missense change affects CACNA1C function (PMID: 25184293, 27502440). 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

Nov 27, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G1911R variant (also known as c.5731G>A), located in coding exon 45 of the CACNA1C gene, results from a G to A substitution at nucleotide position 5731. The glycine at codon 1911 is replaced by arginine, an amino acid with dissimilar properties. This alteration, which is also referenced as c.5875G>C (p.Gly1959Arg), has been reported in an individual suspected to have Timothy syndrome, as well as in a Brugada syndrome cohort and as a secondary cardiac variant in an exome cohort (Ng D et al. Circ Cardiovasc Genet, 2013 Aug;6:337-46; Hennessey JA et al. PLoS One, 2014 Sep;9:e106982; Allegue C et al. PLoS One, 2015 Jul;10:e0133037). Additionally, in vitro studies showed that this alteration may affect protein function (Hennessey JA et al. PLoS One, 2014 Sep;9:e106982; Bai J et al. Sci Rep, 2016 08;6:31262). This amino acid position is well 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	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.018	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Pathogenic	0.41	D
MetaRNN	Uncertain	0.61	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.85	T
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.0	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Pathogenic	0.68
Sift	Benign	0.088	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0030, 0.40, 0.25, 0.81, 0.77, 0.90, 0.015, 0.0010, 0.92, 0.57, 0.95, 0.0	.;B;B;B;P;P;P;P;B;B;P;P;P;P;P;.;P;P;.;.;.;B;.
Vest4		0.60
MVP		0.42
MPC		0.31
ClinPred		0.71	D
GERP RS		4.8
gMVP		0.45

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: rs374528680; hg19: chr12-2795382;