rs786205781

Variant names:

• chr12-2677809-A-G
• rs786205781
• NM_000719.7:c.5033A>G

Variant summary

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

The NM_000719.7(CACNA1C):​c.5033A>G​(p.Glu1678Gly) variant causes a missense change. 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.06

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.5033A>G	p.Glu1678Gly	missense_variant	Exon 41 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5033A>G	p.Glu1678Gly	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.5033A>G	p.Glu1678Gly	missense_variant	Exon 41 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5033A>G	p.Glu1678Gly	missense_variant	Exon 41 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5267A>G	p.Glu1756Gly	missense_variant	Exon 43 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5033A>G	p.Glu1678Gly	missense_variant	Exon 41 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5000A>G	p.Glu1667Gly	missense_variant	Exon 40 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5198A>G	p.Glu1733Gly	missense_variant	Exon 42 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5177A>G	p.Glu1726Gly	missense_variant	Exon 43 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5156A>G	p.Glu1719Gly	missense_variant	Exon 41 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5033A>G	p.Glu1678Gly	missense_variant	Exon 41 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5033A>G	p.Glu1678Gly	missense_variant	Exon 41 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5123A>G	p.Glu1708Gly	missense_variant	Exon 41 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5123A>G	p.Glu1708Gly	missense_variant	Exon 41 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5123A>G	p.Glu1708Gly	missense_variant	Exon 41 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5123A>G	p.Glu1708Gly	missense_variant	Exon 41 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5117A>G	p.Glu1706Gly	missense_variant	Exon 42 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5108A>G	p.Glu1703Gly	missense_variant	Exon 42 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5093A>G	p.Glu1698Gly	missense_variant	Exon 42 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5090A>G	p.Glu1697Gly	missense_variant	Exon 41 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5090A>G	p.Glu1697Gly	missense_variant	Exon 41 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5090A>G	p.Glu1697Gly	missense_variant	Exon 41 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5084A>G	p.Glu1695Gly	missense_variant	Exon 41 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5075A>G	p.Glu1692Gly	missense_variant	Exon 41 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5057A>G	p.Glu1686Gly	missense_variant	Exon 40 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5057A>G	p.Glu1686Gly	missense_variant	Exon 40 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5051A>G	p.Glu1684Gly	missense_variant	Exon 40 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5033A>G	p.Glu1678Gly	missense_variant	Exon 41 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5033A>G	p.Glu1678Gly	missense_variant	Exon 41 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5033A>G	p.Glu1678Gly	missense_variant	Exon 41 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5033A>G	p.Glu1678Gly	missense_variant	Exon 41 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5033A>G	p.Glu1678Gly	missense_variant	Exon 41 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5024A>G	p.Glu1675Gly	missense_variant	Exon 41 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5000A>G	p.Glu1667Gly	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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Oct 28, 2014

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Glu1678Gly (GAG>GGG): c.5033 A>G in exon 41 of the CACNA1C gene (NM_000719.6). The E1678G variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The E1678G variant was not observed in approximately 6,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The E1678G variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in vertebrates. However, in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Furthermore, no missense mutations in nearby residues have been reported, indicating that this region of the protein may be tolerant of change. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in BRUGADA panel(s). -

Long QT syndrome Uncertain:1

Mar 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1678 of the CACNA1C protein (p.Glu1678Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 190708). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1C protein function. 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
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.012	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Benign	0.13
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.70	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	1.0	D
MutationAssessor	Uncertain	2.7	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.65
Sift	Uncertain	0.021	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.34	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.51, 0.065, 0.0010, 0.0090, 0.38, 0.62, 0.71, 0.082, 0.61, 0.57, 0.36, 0.74, 1.0	.;P;B;B;B;B;P;P;P;B;P;P;P;B;P;.;P;P;.;.;.;D;.
Vest4		0.67
MutPred		0.39		.;.;.;.;.;.;.;.;.;.;Loss of solvent accessibility (P = 0.0299);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.83
MPC		0.29
ClinPred		0.90	D
GERP RS		4.6
gMVP		0.79

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: rs786205781; hg19: chr12-2786975;