rs760543068

Variant names:

• chr12-2611975-G-A
• rs760543068
• NM_000719.7:c.3790G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-2611975-G-A
• chr12-2611975-G-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4 BP6 BS2

The NM_000719.7(CACNA1C):​c.3790G>A​(p.Val1264Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,612,952 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 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 6.80

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]

ACMG classification

Verdict is Likely_benign. Variant got -5 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=0.42140487).
• BP6: Variant 12-2611975-G-A is Benign according to our data. Variant chr12-2611975-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 456967.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=2}.
• 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.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3940G>A	p.Val1314Met	missense_variant	Exon 30 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3955G>A	p.Val1319Met	missense_variant	Exon 30 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3850G>A	p.Val1284Met	missense_variant	Exon 30 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3880G>A	p.Val1294Met	missense_variant	Exon 29 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3880G>A	p.Val1294Met	missense_variant	Exon 29 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3880G>A	p.Val1294Met	missense_variant	Exon 29 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3880G>A	p.Val1294Met	missense_variant	Exon 29 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3865G>A	p.Val1289Met	missense_variant	Exon 30 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3850G>A	p.Val1284Met	missense_variant	Exon 30 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3865G>A	p.Val1289Met	missense_variant	Exon 30 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3781G>A	p.Val1261Met	missense_variant	Exon 29 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3790G>A	p.Val1264Met	missense_variant	Exon 29 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*2397G>A		non_coding_transcript_exon_variant	Exon 27 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*2397G>A		3_prime_UTR_variant	Exon 27 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

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: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000560 AC: 14 AN: 250188 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135614

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000319

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: 0.0000176

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.0000199 AC: 29 AN: 1460816 Hom.: 0 Cov.: 29 AF XY: 0.0000179 AC XY: 13 AN XY: 726830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74312

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: 0.0000943

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Jul 05, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Long QT syndrome Uncertain:1

Dec 04, 2024

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 methionine, which is neutral and non-polar, at codon 1264 of the CACNA1C protein (p.Val1264Met). This variant is present in population databases (rs760543068, gnomAD 0.03%), and has an allele count higher than expected for a pathogenic variant. 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: 456967). 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) has been performed 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 Benign:1

Jun 12, 2023

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.42	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	.;.;.;.;.;.;.;.;.;.;.;M;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Pathogenic	0.78
Sift	Benign	0.041	D;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.99, 0.99, 1.0, 0.98	.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.56
MutPred		0.70		.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at F1282 (P = 0.0064);Gain of catalytic residue at F1282 (P = 0.0064);.;.;.;.;.;.;.;.;.;.;
MVP		0.93
MPC		1.6
ClinPred		0.32	T
GERP RS		4.2
gMVP		0.94

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: rs760543068; hg19: chr12-2721141;