12-2679597-G-A

Position:

• chr12-2679597-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The ENST00000399655.6(CACNA1C):​c.5245G>A​(p.Val1749Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000171 in 1,461,452 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1749A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: CACNA1C ENST00000399655.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.94

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29270276).
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5245G>A	p.Val1749Met	missense_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5245G>A	p.Val1749Met	missense_variant	42/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5245G>A	p.Val1749Met	missense_variant	42/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5245G>A	p.Val1749Met	missense_variant	42/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5479G>A	p.Val1827Met	missense_variant	44/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5245G>A	p.Val1749Met	missense_variant	42/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5212G>A	p.Val1738Met	missense_variant	41/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5410G>A	p.Val1804Met	missense_variant	43/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5389G>A	p.Val1797Met	missense_variant	44/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5368G>A	p.Val1790Met	missense_variant	42/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5245G>A	p.Val1749Met	missense_variant	42/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5245G>A	p.Val1749Met	missense_variant	42/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5335G>A	p.Val1779Met	missense_variant	42/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5335G>A	p.Val1779Met	missense_variant	42/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5335G>A	p.Val1779Met	missense_variant	42/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5335G>A	p.Val1779Met	missense_variant	42/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5329G>A	p.Val1777Met	missense_variant	43/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5320G>A	p.Val1774Met	missense_variant	43/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5305G>A	p.Val1769Met	missense_variant	43/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5302G>A	p.Val1768Met	missense_variant	42/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5302G>A	p.Val1768Met	missense_variant	42/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5302G>A	p.Val1768Met	missense_variant	42/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5296G>A	p.Val1766Met	missense_variant	42/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5287G>A	p.Val1763Met	missense_variant	42/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5269G>A	p.Val1757Met	missense_variant	41/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5269G>A	p.Val1757Met	missense_variant	41/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5263G>A	p.Val1755Met	missense_variant	41/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5245G>A	p.Val1749Met	missense_variant	42/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5245G>A	p.Val1749Met	missense_variant	42/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5245G>A	p.Val1749Met	missense_variant	42/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5245G>A	p.Val1749Met	missense_variant	42/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5245G>A	p.Val1749Met	missense_variant	42/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5236G>A	p.Val1746Met	missense_variant	42/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5212G>A	p.Val1738Met	missense_variant	41/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461452 Hom.: 0 Cov.: 31 AF XY: 0.0000179 AC XY: 13 AN XY: 727002

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: 0.0000225

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CACNA1C-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 31, 2023

The CACNA1C c.5245G>A variant is predicted to result in the amino acid substitution p.Val1749Met. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 14, 2020

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with CACNA1C-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with methionine at codon 1749 of the CACNA1C protein (p.Val1749Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Benign	0.95
DEOGEN2	Benign	0.0053	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.00014
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.94	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.29	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	0.69	D
MutationAssessor	Benign	1.4	.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.57	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.36
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;.
Sift4G	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
Polyphen		0.38, 0.82, 0.049, 0.11, 0.11, 0.63, 0.49, 0.087, 0.49, 0.53, 1.0	.;B;P;B;B;B;P;P;B;B;P;P;P;D;P;.;P;P;.;.;.;B;.
Vest4		0.28
MutPred		0.21		.;.;.;.;.;.;.;.;.;.;Gain of phosphorylation at T1802 (P = 0.0806);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.79
MPC		0.65
ClinPred		0.85	D
GERP RS		4.6
gMVP		0.46

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1556109769; hg19: chr12-2788763;