12-2504487-G-A

Position:

• chr12-2504487-G-A

Variant summary

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

The NM_001167623.2(CACNA1C):​c.1165G>A​(p.Val389Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_001167623.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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 I (size 297) in uniprot entity CAC1C_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_001167623.2
• 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_001167623.2	c.1165G>A	p.Val389Ile	missense_variant	8/47	ENST00000399603.6	NP_001161095.1
CACNA1C	NM_000719.7	c.1114-355G>A		intron_variant		ENST00000399655.6	NP_000710.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.1165G>A	p.Val389Ile	missense_variant	8/47	5	NM_001167623.2	ENSP00000382512
CACNA1C	ENST00000399655.6	c.1114-355G>A		intron_variant		1	NM_000719.7	ENSP00000382563

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

research

Biesecker Lab/Clinical Genomics Section, National Institutes of Health

Jun 24, 2013

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Benign	0.49
DEOGEN2	Benign	0.0045	.;.;.;T;.
Eigen	Benign	-0.24
Eigen_PC	Benign	0.046
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.49	T;T;T;T;T
MetaSVM	Uncertain	0.22	D
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
PROVEAN	Benign	0.18	N;N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	1.0	T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T
Polyphen		0.0	B;.;.;.;B
Vest4		0.66
MutPred		0.67		Loss of catalytic residue at V389 (P = 0.094);Loss of catalytic residue at V389 (P = 0.094);Loss of catalytic residue at V389 (P = 0.094);Loss of catalytic residue at V389 (P = 0.094);Loss of catalytic residue at V389 (P = 0.094);
MVP		0.79
ClinPred		0.84	D
GERP RS		5.0

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: rs202180580; hg19: chr12-2613653;