chr12-2677207-G-A

Variant names:

• chr12-2677207-G-A
• rs370432385
• NM_000719.7:c.4942G>A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_000719.7(CACNA1C):​c.4942G>A​(p.Ala1648Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000607 in 1,613,592 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 3.62

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 -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=0.08336723).
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4942G>A	p.Ala1648Thr	missense_variant	Exon 40 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4942G>A	p.Ala1648Thr	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.4942G>A	p.Ala1648Thr	missense_variant	Exon 40 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4942G>A	p.Ala1648Thr	missense_variant	Exon 40 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5176G>A	p.Ala1726Thr	missense_variant	Exon 42 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4942G>A	p.Ala1648Thr	missense_variant	Exon 40 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4909G>A	p.Ala1637Thr	missense_variant	Exon 39 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5107G>A	p.Ala1703Thr	missense_variant	Exon 41 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5086G>A	p.Ala1696Thr	missense_variant	Exon 42 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 40 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4942G>A	p.Ala1648Thr	missense_variant	Exon 40 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4942G>A	p.Ala1648Thr	missense_variant	Exon 40 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5032G>A	p.Ala1678Thr	missense_variant	Exon 40 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5032G>A	p.Ala1678Thr	missense_variant	Exon 40 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5032G>A	p.Ala1678Thr	missense_variant	Exon 40 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5032G>A	p.Ala1678Thr	missense_variant	Exon 40 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5026G>A	p.Ala1676Thr	missense_variant	Exon 41 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5017G>A	p.Ala1673Thr	missense_variant	Exon 41 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5002G>A	p.Ala1668Thr	missense_variant	Exon 41 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4999G>A	p.Ala1667Thr	missense_variant	Exon 40 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4999G>A	p.Ala1667Thr	missense_variant	Exon 40 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4999G>A	p.Ala1667Thr	missense_variant	Exon 40 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4993G>A	p.Ala1665Thr	missense_variant	Exon 40 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4984G>A	p.Ala1662Thr	missense_variant	Exon 40 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4966G>A	p.Ala1656Thr	missense_variant	Exon 39 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4966G>A	p.Ala1656Thr	missense_variant	Exon 39 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4960G>A	p.Ala1654Thr	missense_variant	Exon 39 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4942G>A	p.Ala1648Thr	missense_variant	Exon 40 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4942G>A	p.Ala1648Thr	missense_variant	Exon 40 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4942G>A	p.Ala1648Thr	missense_variant	Exon 40 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4942G>A	p.Ala1648Thr	missense_variant	Exon 40 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4942G>A	p.Ala1648Thr	missense_variant	Exon 40 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4933G>A	p.Ala1645Thr	missense_variant	Exon 40 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4909G>A	p.Ala1637Thr	missense_variant	Exon 39 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 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: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000725 AC: 18 AN: 248180 Hom.: 0 AF XY: 0.0000891 AC XY: 12 AN XY: 134708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0000997

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.000142

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000561 AC: 82 AN: 1461386 Hom.: 0 Cov.: 31 AF XY: 0.0000578 AC XY: 42 AN XY: 726932

Gnomad4 AFR exome AF: 0.0000597

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: 0.0000188

Gnomad4 NFE exome AF: 0.0000648

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152206 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74338

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: 0.000188

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.0000827 AC: 10

EpiCase AF: 0.000382

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Jan 24, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in probands with a history of sudden death (PMID: 27930701, 30279520) and in patient referred for a suspected arrhythmogenic disorder (PMID: 31737537); also described as p.(A1696T) due to the use of an alternate transcript; In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies in HEK293 cells suggest that this variant causes a dramatic reduction in current density (PMID: 34999275); This variant is associated with the following publications: (PMID: 30279520, 31737537, 27930701, 34999275) -

Nov 18, 2014

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CACNA1C: PP2 -

Timothy syndrome Uncertain:1

Apr 13, 2017

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Long QT syndrome Benign:1

Jan 05, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Dec 20, 2024

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	Benign	-0.22	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Benign	0.88
DEOGEN2	Benign	0.0029	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.083	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	0.11	D
MutationAssessor	Benign	0.28	.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.88	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.40
Sift	Benign	0.86	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.68	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.054, 0.0020, 0.017, 0.0090, 0.045, 0.026, 0.046, 0.047, 0.061, 0.030, 0.10, 0.067, 0.37, 0.20, 0.0080	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.23
MVP		0.80
MPC		1.0
ClinPred		0.084	T
GERP RS		3.4
gMVP		0.80

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: rs370432385; hg19: chr12-2786373; COSMIC: COSV59706141; COSMIC: COSV59706141;