rs215976

chr12-2585472-C-Gchr12-2585472-C-T

Variant summary

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

The NM_000719.7(CACNA1C):c.2436C>G(p.Asp812Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D812D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.487

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CACNA1C

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.2436C>G	p.Asp812Glu	missense_variant	17/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.2436C>G	p.Asp812Glu	missense_variant	17/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2436C>G	p.Asp812Glu	missense_variant	17/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.2436C>G	p.Asp812Glu	missense_variant	17/47	1	NM_000719.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
CardioboostArm	Benign	0.000024
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Benign	8.0
Dann	Benign	0.96
DEOGEN2	Benign	0.021	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.72
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.49	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	0.30	D
MutationTaster	Benign	0.0014	P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P;P
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.3	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	0.44
Sift	Benign	0.16	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	0.43	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.99, 1.0, 0.0080, 0.95, 0.096, 1.0, 0.086, 0.99, 0.95, 1.0	.;D;D;B;P;B;D;D;D;B;D;D;D;P;D;D;.;D;D;.;D;.;D
Vest4		0.21
MutPred		0.21		.;Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);Gain of catalytic residue at P816 (P = 5e-04);
MVP		0.86
MPC		1.2
ClinPred		0.67	D
GERP RS		-0.65
gMVP		0.32

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: rs215976; hg19: chr12-2694638;