rs115216455

Positions:

• chr12-2679491-C-A
• chr12-2679491-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000719.7(CACNA1C):​c.5139C>A​(p.Asp1713Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D1713D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.395

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.23914832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5139C>A	p.Asp1713Glu	missense_variant	42/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5139C>A	p.Asp1713Glu	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.5139C>A	p.Asp1713Glu	missense_variant	42/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5139C>A	p.Asp1713Glu	missense_variant	42/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5373C>A	p.Asp1791Glu	missense_variant	44/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5139C>A	p.Asp1713Glu	missense_variant	42/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5106C>A	p.Asp1702Glu	missense_variant	41/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5304C>A	p.Asp1768Glu	missense_variant	43/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5283C>A	p.Asp1761Glu	missense_variant	44/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5262C>A	p.Asp1754Glu	missense_variant	42/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5139C>A	p.Asp1713Glu	missense_variant	42/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5139C>A	p.Asp1713Glu	missense_variant	42/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5229C>A	p.Asp1743Glu	missense_variant	42/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5229C>A	p.Asp1743Glu	missense_variant	42/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5229C>A	p.Asp1743Glu	missense_variant	42/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5229C>A	p.Asp1743Glu	missense_variant	42/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5223C>A	p.Asp1741Glu	missense_variant	43/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5214C>A	p.Asp1738Glu	missense_variant	43/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5199C>A	p.Asp1733Glu	missense_variant	43/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5196C>A	p.Asp1732Glu	missense_variant	42/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5196C>A	p.Asp1732Glu	missense_variant	42/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5196C>A	p.Asp1732Glu	missense_variant	42/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5190C>A	p.Asp1730Glu	missense_variant	42/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5181C>A	p.Asp1727Glu	missense_variant	42/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5163C>A	p.Asp1721Glu	missense_variant	41/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5163C>A	p.Asp1721Glu	missense_variant	41/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5157C>A	p.Asp1719Glu	missense_variant	41/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5139C>A	p.Asp1713Glu	missense_variant	42/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5139C>A	p.Asp1713Glu	missense_variant	42/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5139C>A	p.Asp1713Glu	missense_variant	42/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5139C>A	p.Asp1713Glu	missense_variant	42/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5139C>A	p.Asp1713Glu	missense_variant	42/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5130C>A	p.Asp1710Glu	missense_variant	42/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5106C>A	p.Asp1702Glu	missense_variant	41/46			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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2022

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. 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. ClinVar contains an entry for this variant (Variation ID: 663042). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 1713 of the CACNA1C protein (p.Asp1713Glu). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.013	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.78	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.24	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	0.0069	D
MutationAssessor	Benign	1.3	.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.5	N;N;N;N;D;N;N;N;N;N;D;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Benign	0.26
Sift	Benign	0.13	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;.
Sift4G	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.012, 0.0010, 0.0050, 0.0040, 0.11, 0.019, 0.010, 0.0030, 0.065, 0.094, 0.033, 0.039	.;B;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;B;.
Vest4		0.26
MutPred		0.30		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at S1756 (P = 0.0057);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.74
MPC		0.18
ClinPred		0.38	T
GERP RS		2.6
gMVP		0.26

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: rs115216455; hg19: chr12-2788657;