rs1060503446

Positions:

• chr12-2593315-G-C
• chr12-2593315-G-T

Variant summary

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

The NM_000719.7(CACNA1C):​c.2633G>C​(p.Ser878Thr) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S878I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.67

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.34492218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.2633G>C	p.Ser878Thr	missense_variant	19/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.2633G>C	p.Ser878Thr	missense_variant	19/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2633G>C	p.Ser878Thr	missense_variant	19/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.2633G>C	p.Ser878Thr	missense_variant	19/47	1	NM_000719.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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 20, 2016

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 serine with threonine at codon 878 of the CACNA1C protein (p.Ser878Thr). The serine residue is moderately conserved and there is a small physicochemical difference between serine and threonine. 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. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.081	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	0.044
Eigen_PC	Benign	0.17
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Uncertain	0.19	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	Pathogenic	1.0	D
MutationAssessor	Benign	1.7	.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.
MutationTaster	Benign	0.75	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	0.72	T
PROVEAN	Uncertain	-2.6	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.38
Sift	Benign	0.099	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	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010, 0.0, 0.10, 0.0090, 0.21, 0.0020, 0.99, 0.0050, 0.0080	.;B;B;B;B;B;B;B;B;B;B;B;B;B;D;B;.;B;B;.;B;.;B
Vest4		0.37
MutPred		0.40		.;Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);Gain of catalytic residue at E876 (P = 0.0061);
MVP		0.89
MPC		1.7
ClinPred		0.95	D
GERP RS		4.9
gMVP		0.74

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: rs1060503446; hg19: chr12-2702481;