12-2567652-G-T

Position:

• chr12-2567652-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_000719.7(CACNA1C):​c.1753G>T​(p.Val585Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. V585M) 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: 5.88

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 5 ACMG points.

• PM1: In a repeat II (size 246) in uniprot entity CAC1C_HUMAN there are 24 pathogenic changes around while only 10 benign (71%) in NM_000719.7
• 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	UniProt
CACNA1C	NM_000719.7	c.1753G>T	p.Val585Leu	missense_variant	13/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.1753G>T	p.Val585Leu	missense_variant	13/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1753G>T	p.Val585Leu	missense_variant	13/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.1753G>T	p.Val585Leu	missense_variant	13/47	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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

May 12, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.62	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	1.1	D
MutationAssessor	Benign	0.84	.;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	Pathogenic	0.85	D
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;N
REVEL	Pathogenic	0.75
Sift	Uncertain	0.026	D;D;T;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.29	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, 0.96, 0.98, 0.68, 0.94, 1.0, 0.98, 0.99	.;D;D;D;P;P;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.70
MutPred		0.56		.;Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);Gain of catalytic residue at Q581 (P = 0.0011);
MVP		0.81
MPC		2.0
ClinPred		0.96	D
GERP RS		5.1
gMVP		0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-2676818;