rs1060503447

Positions:

• chr12-2584611-T-C

Variant summary

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

The NM_000719.7(CACNA1C):​c.2333T>C​(p.Leu778Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,870 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: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.92

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2333T>C	p.Leu778Pro	missense_variant	16/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2333T>C	p.Leu778Pro	missense_variant	16/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2333T>C	p.Leu778Pro	missense_variant	16/47	5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.2333T>C	p.Leu778Pro	missense_variant	16/47	1	NM_000719.7	ENSP00000382563

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457870 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 725218

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: 0.00000180

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

This sequence change replaces leucine with proline at codon 778 of the CACNA1C protein (p.Leu778Pro). The leucine residue is moderately conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CACNA1C function (PMID: 19061337, 23145875). 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	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.087	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.97	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.71	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	0.94	D
MutationAssessor	Benign	1.5	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.7	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.74
Sift	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Sift4G	Benign	0.24	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		1.0, 1.0, 0.012, 0.020, 0.0040, 0.027, 1.0, 1.0	.;D;D;B;B;B;D;D;D;B;D;D;D;D;D;D;.;D;D;.;D;.;D
Vest4		0.69
MutPred		0.48		.;Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);Gain of glycosylation at L778 (P = 0.0247);
MVP		0.96
MPC		1.7
ClinPred		0.91	D
GERP RS		4.7
gMVP		0.96

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060503447; hg19: chr12-2693777;