chr12-2053565-G-C

Position:

• chr12-2053565-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000719.7(CACNA1C):​c.3G>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: CACNA1C NM_000719.7 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.87

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7	c.3G>C	p.Met1?	start_lost	1/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.3G>C	p.Met1?	start_lost	1/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3G>C	p.Met1?	start_lost	1/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.3G>C	p.Met1?	start_lost	1/47	1	NM_000719.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

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

Mar 05, 2022

Not observed at significant frequency in large population cohorts (gnomAD); Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; however, in the absence of functional evidence the actual effect of this sequence change is unknown; 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	0.63	D
BayesDel_noAF	Pathogenic	0.45
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Benign	0.14
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.91	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	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	0.88	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	-0.74	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	0.71
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.39, 0.025, 0.11, 0.66	.;B;.;B;B;B;B;B;B;B;B;P;B;B;B;B;.;B;B;.;.;.;.
Vest4		0.89
MutPred		0.98		Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);Gain of catalytic residue at T6 (P = 0.0107);
MVP		0.98
ClinPred		0.99	D
GERP RS		3.0
gMVP		0.58

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: chr12-2162731;