12-2679510-C-G

Variant names:

• chr12-2679510-C-G
• rs1008863902
• NM_000719.7:c.5158C>G

Variant summary

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

The NM_000719.7(CACNA1C):​c.5158C>G​(p.Gln1720Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,458,790 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.50

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.5158C>G	p.Gln1720Glu	missense_variant	Exon 42 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.5158C>G	p.Gln1720Glu	missense_variant	Exon 42 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.5158C>G	p.Gln1720Glu	missense_variant	Exon 42 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.5158C>G	p.Gln1720Glu	missense_variant	Exon 42 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.5392C>G	p.Gln1798Glu	missense_variant	Exon 44 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.5158C>G	p.Gln1720Glu	missense_variant	Exon 42 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.5125C>G	p.Gln1709Glu	missense_variant	Exon 41 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.5323C>G	p.Gln1775Glu	missense_variant	Exon 43 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.5302C>G	p.Gln1768Glu	missense_variant	Exon 44 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.5281C>G	p.Gln1761Glu	missense_variant	Exon 42 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.5158C>G	p.Gln1720Glu	missense_variant	Exon 42 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.5158C>G	p.Gln1720Glu	missense_variant	Exon 42 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.5248C>G	p.Gln1750Glu	missense_variant	Exon 42 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.5248C>G	p.Gln1750Glu	missense_variant	Exon 42 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.5248C>G	p.Gln1750Glu	missense_variant	Exon 42 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.5248C>G	p.Gln1750Glu	missense_variant	Exon 42 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.5242C>G	p.Gln1748Glu	missense_variant	Exon 43 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.5233C>G	p.Gln1745Glu	missense_variant	Exon 43 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.5218C>G	p.Gln1740Glu	missense_variant	Exon 43 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.5215C>G	p.Gln1739Glu	missense_variant	Exon 42 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.5215C>G	p.Gln1739Glu	missense_variant	Exon 42 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.5215C>G	p.Gln1739Glu	missense_variant	Exon 42 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.5209C>G	p.Gln1737Glu	missense_variant	Exon 42 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.5200C>G	p.Gln1734Glu	missense_variant	Exon 42 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.5182C>G	p.Gln1728Glu	missense_variant	Exon 41 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.5182C>G	p.Gln1728Glu	missense_variant	Exon 41 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.5176C>G	p.Gln1726Glu	missense_variant	Exon 41 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.5158C>G	p.Gln1720Glu	missense_variant	Exon 42 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.5158C>G	p.Gln1720Glu	missense_variant	Exon 42 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.5158C>G	p.Gln1720Glu	missense_variant	Exon 42 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.5158C>G	p.Gln1720Glu	missense_variant	Exon 42 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.5158C>G	p.Gln1720Glu	missense_variant	Exon 42 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.5149C>G	p.Gln1717Glu	missense_variant	Exon 42 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.5125C>G	p.Gln1709Glu	missense_variant	Exon 41 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458790 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725306

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

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

Nov 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 1720 of the CACNA1C protein (p.Gln1720Glu). 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: 411724). Invitae Evidence 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 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	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.17	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	Uncertain	0.55	D
MutationAssessor	Uncertain	2.7	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.1	N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;.
REVEL	Uncertain	0.51
Sift	Benign	0.099	T;T;T;T;T;T;D;D;D;T;T;T;T;D;T;D;T;D;T;D;D;D;.
Sift4G	Benign	0.67	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.98, 0.18, 0.85, 0.50, 0.99, 0.99, 0.72, 0.98, 0.97, 0.99, 0.92	.;D;B;P;P;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;P;.
Vest4		0.63
MutPred		0.34		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at R1763 (P = 0.052);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.81
MPC		0.24
ClinPred		0.81	D
GERP RS		4.6
gMVP		0.61

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: rs1008863902; hg19: chr12-2788676;