rs1556050949

Variant names:

• chr12-2677815-A-G
• rs1556050949
• NM_000719.7:c.5039A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000719.7(CACNA1C):​c.5039A>G​(p.Asp1680Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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: 7.27

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5039A>G	p.Asp1680Gly	missense_variant	Exon 41 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5039A>G	p.Asp1680Gly	missense_variant	Exon 41 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5039A>G	p.Asp1680Gly	missense_variant	Exon 41 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5039A>G	p.Asp1680Gly	missense_variant	Exon 41 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5273A>G	p.Asp1758Gly	missense_variant	Exon 43 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5039A>G	p.Asp1680Gly	missense_variant	Exon 41 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5006A>G	p.Asp1669Gly	missense_variant	Exon 40 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5204A>G	p.Asp1735Gly	missense_variant	Exon 42 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5183A>G	p.Asp1728Gly	missense_variant	Exon 43 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5162A>G	p.Asp1721Gly	missense_variant	Exon 41 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5039A>G	p.Asp1680Gly	missense_variant	Exon 41 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5039A>G	p.Asp1680Gly	missense_variant	Exon 41 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5129A>G	p.Asp1710Gly	missense_variant	Exon 41 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5129A>G	p.Asp1710Gly	missense_variant	Exon 41 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5129A>G	p.Asp1710Gly	missense_variant	Exon 41 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5129A>G	p.Asp1710Gly	missense_variant	Exon 41 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5123A>G	p.Asp1708Gly	missense_variant	Exon 42 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5114A>G	p.Asp1705Gly	missense_variant	Exon 42 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5099A>G	p.Asp1700Gly	missense_variant	Exon 42 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5096A>G	p.Asp1699Gly	missense_variant	Exon 41 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5096A>G	p.Asp1699Gly	missense_variant	Exon 41 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5096A>G	p.Asp1699Gly	missense_variant	Exon 41 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5090A>G	p.Asp1697Gly	missense_variant	Exon 41 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5081A>G	p.Asp1694Gly	missense_variant	Exon 41 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5063A>G	p.Asp1688Gly	missense_variant	Exon 40 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5063A>G	p.Asp1688Gly	missense_variant	Exon 40 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5057A>G	p.Asp1686Gly	missense_variant	Exon 40 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5039A>G	p.Asp1680Gly	missense_variant	Exon 41 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5039A>G	p.Asp1680Gly	missense_variant	Exon 41 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5039A>G	p.Asp1680Gly	missense_variant	Exon 41 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5039A>G	p.Asp1680Gly	missense_variant	Exon 41 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5039A>G	p.Asp1680Gly	missense_variant	Exon 41 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5030A>G	p.Asp1677Gly	missense_variant	Exon 41 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5006A>G	p.Asp1669Gly	missense_variant	Exon 40 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Aug 21, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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 aspartic acid with glycine at codon 1680 of the CACNA1C protein (p.Asp1680Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.21
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.51	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.88	D
MutationAssessor	Uncertain	2.4	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-4.1	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Uncertain	0.60
Sift	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;T;T;D;D;D;.
Sift4G	Benign	0.079	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D
Polyphen		0.49, 0.17, 0.22, 0.12, 0.55, 0.60, 0.71, 0.68, 0.76, 0.73, 0.77, 0.96	.;P;B;B;B;P;P;P;P;P;P;P;P;P;P;.;P;P;.;.;.;D;.
Vest4		0.52
MutPred		0.26		.;.;.;.;.;.;.;.;.;.;Gain of methylation at K1729 (P = 0.0657);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.85
MPC		0.27
ClinPred		0.93	D
GERP RS		4.6
gMVP		0.75

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: rs1556050949; hg19: chr12-2786981;