rs763738559

Positions:

• chr12-2567652-G-A
• chr12-2567652-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP2 BS2

The NM_000719.7(CACNA1C):​c.1753G>A​(p.Val585Met) variant causes a missense change. The variant allele was found at a frequency of 0.000062 in 1,613,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000061 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 5.88

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 -1 ACMG points.

• PM1: In a repeat II (size 246) in uniprot entity CAC1C_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_000719.7
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with 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 GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1753G>A	p.Val585Met	missense_variant	13/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1753G>A	p.Val585Met	missense_variant	13/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1753G>A	p.Val585Met	missense_variant	13/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1753G>A	p.Val585Met	missense_variant	13/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1843G>A	p.Val615Met	missense_variant	13/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1753G>A	p.Val585Met	missense_variant	13/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1753G>A	p.Val585Met	missense_variant	13/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1918G>A	p.Val640Met	missense_variant	14/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1753G>A	p.Val585Met	missense_variant	13/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1753G>A	p.Val585Met	missense_variant	13/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1753G>A	p.Val585Met	missense_variant	13/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1753G>A	p.Val585Met	missense_variant	13/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1843G>A	p.Val615Met	missense_variant	13/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1843G>A	p.Val615Met	missense_variant	13/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1843G>A	p.Val615Met	missense_variant	13/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1843G>A	p.Val615Met	missense_variant	13/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1753G>A	p.Val585Met	missense_variant	13/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1828G>A	p.Val610Met	missense_variant	14/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1753G>A	p.Val585Met	missense_variant	13/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1753G>A	p.Val585Met	missense_variant	13/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1753G>A	p.Val585Met	missense_variant	13/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1753G>A	p.Val585Met	missense_variant	13/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1753G>A	p.Val585Met	missense_variant	13/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1828G>A	p.Val610Met	missense_variant	14/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1753G>A	p.Val585Met	missense_variant	13/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1753G>A	p.Val585Met	missense_variant	13/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1753G>A	p.Val585Met	missense_variant	13/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1753G>A	p.Val585Met	missense_variant	13/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1753G>A	p.Val585Met	missense_variant	13/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1753G>A	p.Val585Met	missense_variant	13/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1753G>A	p.Val585Met	missense_variant	13/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1753G>A	p.Val585Met	missense_variant	13/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1744G>A	p.Val582Met	missense_variant	13/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1753G>A	p.Val585Met	missense_variant	13/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*360G>A		non_coding_transcript_exon_variant	11/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*360G>A		3_prime_UTR_variant	11/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152148 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000323 AC: 8 AN: 247354 Hom.: 0 AF XY: 0.00000746 AC XY: 1 AN XY: 134076

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: 0.0000626

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000609 AC: 89 AN: 1460892 Hom.: 0 Cov.: 31 AF XY: 0.0000537 AC XY: 39 AN XY: 726608

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: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000765

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74324

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 30, 2020	Has been reported in an individual with sudden unexplained death at 36 years of age, and cardiac findings on autopsy showed interstitial fibrosis and myocyte hypertrophy (Shanks et al., 2018); however, a frameshift variant in the A-band of the TTN gene was also identified and no family history or segregation details were reported.; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29915097) -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 18, 2021

- -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 01, 2022

This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 585 of the CACNA1C protein (p.Val585Met). This variant is present in population databases (rs763738559, gnomAD 0.007%). 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: 519274). 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) performed at Invitae indicates that this missense variant is not expected to disrupt 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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

This alteration is classified as likely 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	0.15	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.44	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	0.95	D
MutationAssessor	Benign	-0.17	.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N;N;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.6	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.63
Sift	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.26	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, 1.0, 0.95, 0.86, 0.98	.;D;D;P;D;P;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.44
MVP		0.77
MPC		1.8
ClinPred		0.46	T
GERP RS		5.1
gMVP		0.85

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: rs763738559; hg19: chr12-2676818; COSMIC: COSV59768764; COSMIC: COSV59768764;