rs781440831

Variant names:

• chr12-2607009-G-A
• rs781440831
• NM_000719.7:c.3235G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PP2 PP3_Moderate BS2

The NM_000719.7(CACNA1C):​c.3235G>A​(p.Gly1079Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.75

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-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

ACMG classification

Verdict is Likely_benign. Variant got -1 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.87
• BS2: High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3385G>A	p.Gly1129Arg	missense_variant	Exon 27 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3400G>A	p.Gly1134Arg	missense_variant	Exon 27 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3295G>A	p.Gly1099Arg	missense_variant	Exon 27 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3325G>A	p.Gly1109Arg	missense_variant	Exon 26 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3325G>A	p.Gly1109Arg	missense_variant	Exon 26 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3325G>A	p.Gly1109Arg	missense_variant	Exon 26 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3325G>A	p.Gly1109Arg	missense_variant	Exon 26 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3310G>A	p.Gly1104Arg	missense_variant	Exon 27 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3295G>A	p.Gly1099Arg	missense_variant	Exon 27 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3310G>A	p.Gly1104Arg	missense_variant	Exon 27 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3226G>A	p.Gly1076Arg	missense_variant	Exon 26 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3235G>A	p.Gly1079Arg	missense_variant	Exon 26 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1842G>A		non_coding_transcript_exon_variant	Exon 24 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1842G>A		3_prime_UTR_variant	Exon 24 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000803 AC: 2 AN: 249218 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135220

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461686 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:2

Apr 03, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Dec 03, 2021

AiLife Diagnostics, AiLife Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Uncertain:1

Mar 20, 2023

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 1079 of the CACNA1C protein (p.Gly1079Arg). This variant is present in population databases (rs781440831, 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: 456960). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1C protein function. 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 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G1079R variant (also known as c.3235G>A), located in coding exon 26 of the CACNA1C gene, results from a G to A substitution at nucleotide position 3235. The glycine at codon 1079 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.74	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.9	.;.;.;.;.;.;.;.;.;.;.;M;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.5	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.025	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.014	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 1.0, 0.96, 0.72	.;D;D;D;D;D;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.74
MutPred		0.64		.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at D1102 (P = 0.0778);Gain of catalytic residue at D1102 (P = 0.0778);.;.;.;.;.;.;.;.;.;.;
MVP		0.97
MPC		2.0
ClinPred		1.0	D
GERP RS		4.9
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs781440831; hg19: chr12-2716175;