NM_000719.7:c.4837G>T

Variant names:

• chr12-2677102-G-T
• rs757629968
• NM_000719.7:c.4837G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000719.7(CACNA1C):​c.4837G>T​(p.Val1613Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. V1613I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.15
• Publications: 0 publications found

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]

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4837G>T	p.Val1613Phe	missense_variant	Exon 40 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4837G>T	p.Val1613Phe	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.4837G>T	p.Val1613Phe	missense_variant	Exon 40 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4837G>T	p.Val1613Phe	missense_variant	Exon 40 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5071G>T	p.Val1691Phe	missense_variant	Exon 42 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4837G>T	p.Val1613Phe	missense_variant	Exon 40 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4804G>T	p.Val1602Phe	missense_variant	Exon 39 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5002G>T	p.Val1668Phe	missense_variant	Exon 41 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4981G>T	p.Val1661Phe	missense_variant	Exon 42 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4960G>T	p.Val1654Phe	missense_variant	Exon 40 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4837G>T	p.Val1613Phe	missense_variant	Exon 40 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4837G>T	p.Val1613Phe	missense_variant	Exon 40 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4927G>T	p.Val1643Phe	missense_variant	Exon 40 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4927G>T	p.Val1643Phe	missense_variant	Exon 40 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4927G>T	p.Val1643Phe	missense_variant	Exon 40 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4927G>T	p.Val1643Phe	missense_variant	Exon 40 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4921G>T	p.Val1641Phe	missense_variant	Exon 41 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4912G>T	p.Val1638Phe	missense_variant	Exon 41 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4897G>T	p.Val1633Phe	missense_variant	Exon 41 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4894G>T	p.Val1632Phe	missense_variant	Exon 40 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4894G>T	p.Val1632Phe	missense_variant	Exon 40 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4894G>T	p.Val1632Phe	missense_variant	Exon 40 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4888G>T	p.Val1630Phe	missense_variant	Exon 40 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4879G>T	p.Val1627Phe	missense_variant	Exon 40 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4861G>T	p.Val1621Phe	missense_variant	Exon 39 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4861G>T	p.Val1621Phe	missense_variant	Exon 39 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4855G>T	p.Val1619Phe	missense_variant	Exon 39 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4837G>T	p.Val1613Phe	missense_variant	Exon 40 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4837G>T	p.Val1613Phe	missense_variant	Exon 40 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4837G>T	p.Val1613Phe	missense_variant	Exon 40 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4837G>T	p.Val1613Phe	missense_variant	Exon 40 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4837G>T	p.Val1613Phe	missense_variant	Exon 40 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4828G>T	p.Val1610Phe	missense_variant	Exon 40 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4804G>T	p.Val1602Phe	missense_variant	Exon 39 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

May 06, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine with phenylalanine at codon 1613 of the CACNA1C protein (p.Val1613Phe). The valine residue is highly conserved and there is a small physicochemical difference between valine and phenylalanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA1C-related conditions. 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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Uncertain	0.87
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.82	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.6	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		8.1
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.026	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, 0.98, 0.90, 0.92, 0.97, 0.89, 0.86, 0.91, 0.84, 0.14	.;D;D;D;D;P;P;D;D;P;P;P;D;P;P;.;P;P;.;.;.;B;.
Vest4		0.78
MutPred		0.61		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at E1660 (P = 0.0024);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.77
MPC		2.5
ClinPred		0.99	D
GERP RS		4.3
gMVP		0.98
Mutation Taster		=6/94	disease causing

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

Other links and lift over

dbSNP: rs757629968; hg19: chr12-2786268;