NM_000719.7:c.5924A>C

Variant names:

• chr12-2688586-A-C
• rs1556308664
• NM_000719.7:c.5924A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_000719.7(CACNA1C):​c.5924A>C​(p.Glu1975Ala) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.56

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34057632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.5924A>C	p.Glu1975Ala	missense_variant	Exon 46 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5924A>C	p.Glu1975Ala	missense_variant	Exon 46 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5924A>C	p.Glu1975Ala	missense_variant	Exon 46 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5924A>C	p.Glu1975Ala	missense_variant	Exon 46 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.6263A>C	p.Glu2088Ala	missense_variant	Exon 49 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.6137A>C	p.Glu2046Ala	missense_variant	Exon 47 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.6104A>C	p.Glu2035Ala	missense_variant	Exon 46 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.6089A>C	p.Glu2030Ala	missense_variant	Exon 47 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.6068A>C	p.Glu2023Ala	missense_variant	Exon 48 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.6047A>C	p.Glu2016Ala	missense_variant	Exon 46 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.6029A>C	p.Glu2010Ala	missense_variant	Exon 47 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.6029A>C	p.Glu2010Ala	missense_variant	Exon 47 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.6014A>C	p.Glu2005Ala	missense_variant	Exon 46 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.6014A>C	p.Glu2005Ala	missense_variant	Exon 46 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.6014A>C	p.Glu2005Ala	missense_variant	Exon 46 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.6014A>C	p.Glu2005Ala	missense_variant	Exon 46 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.6008A>C	p.Glu2003Ala	missense_variant	Exon 47 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5999A>C	p.Glu2000Ala	missense_variant	Exon 47 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5984A>C	p.Glu1995Ala	missense_variant	Exon 47 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5981A>C	p.Glu1994Ala	missense_variant	Exon 46 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5981A>C	p.Glu1994Ala	missense_variant	Exon 46 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5981A>C	p.Glu1994Ala	missense_variant	Exon 46 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5975A>C	p.Glu1992Ala	missense_variant	Exon 46 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5966A>C	p.Glu1989Ala	missense_variant	Exon 46 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5948A>C	p.Glu1983Ala	missense_variant	Exon 45 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5948A>C	p.Glu1983Ala	missense_variant	Exon 45 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5942A>C	p.Glu1981Ala	missense_variant	Exon 45 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5924A>C	p.Glu1975Ala	missense_variant	Exon 46 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5924A>C	p.Glu1975Ala	missense_variant	Exon 46 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5924A>C	p.Glu1975Ala	missense_variant	Exon 46 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5924A>C	p.Glu1975Ala	missense_variant	Exon 46 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5924A>C	p.Glu1975Ala	missense_variant	Exon 46 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5915A>C	p.Glu1972Ala	missense_variant	Exon 46 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5891A>C	p.Glu1964Ala	missense_variant	Exon 45 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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

Mar 18, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. 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. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CACNA1C-related disease. This sequence change replaces glutamic acid with alanine at codon 1975 of the CACNA1C protein (p.Glu1975Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.053
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.51	T
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Benign	0.17
Sift	Uncertain	0.020	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.17	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.14, 0.0080, 0.034, 0.0010, 0.51, 0.20, 0.30, 0.39, 0.70, 0.69, 0.68	.;B;B;B;B;P;B;B;B;B;B;B;B;P;B;.;B;P;.;.;.;P;.
Vest4		0.43
MVP		0.49
MPC		0.26
ClinPred		0.87	D
GERP RS		5.2
gMVP		0.53

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: rs1556308664; hg19: chr12-2797752;