rs369680588

Variant names:

• chr12-2512942-G-C
• rs369680588
• NM_000719.7:c.1348G>C

Your query was ambiguous. Multiple possible variants found:

• chr12-2512942-G-C
• chr12-2512942-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP2 BS2

The NM_000719.7(CACNA1C):​c.1348G>C​(p.Glu450Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,458,662 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.14

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 122) in uniprot entity CAC1C_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in NM_000719.7
• 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.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.1438G>C	p.Glu480Gln	missense_variant	Exon 9 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.1438G>C	p.Glu480Gln	missense_variant	Exon 9 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.1438G>C	p.Glu480Gln	missense_variant	Exon 9 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.1438G>C	p.Glu480Gln	missense_variant	Exon 9 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.1438G>C	p.Glu480Gln	missense_variant	Exon 9 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.1438G>C	p.Glu480Gln	missense_variant	Exon 9 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.1339G>C	p.Glu447Gln	missense_variant	Exon 9 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.1348G>C	p.Glu450Gln	missense_variant	Exon 9 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.1113+19556G>C		intron_variant	Intron 7 of 26	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1458662 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725186

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: 0.00000810

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Sep 28, 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 glutamine, which is neutral and polar, at codon 450 of the CACNA1C protein (p.Glu450Gln). 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: 411717). 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) indicates that this missense variant is expected to disrupt CACNA1C protein function with a positive predictive value of 80%. 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	0.070
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.059	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.64	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	0.97	D
MutationAssessor	Uncertain	2.5	.;M;.;M;M;M;M;M;M;M;M;M;M;M;M;M;.;M;M;M;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.5	D;D;D;N;D;D;D;D;D;N;D;D;D;D;D;D;D;N;D;D;D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.018	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.084	T;T;D;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 0.73, 0.74, 0.97, 1.0, 0.75, 1.0	.;D;.;P;P;D;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.54
MVP		0.87
MPC		1.7
ClinPred		0.98	D
GERP RS		4.4
gMVP		0.84

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: rs369680588; hg19: chr12-2622108;