12-2053565-G-T

Variant summary

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

The NM_000719.7(CACNA1C):c.3G>T(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000692 in 1,445,040 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• 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>T	p.Met1?	start_lost	1/47	ENST00000399655.6
CACNA1C	NM_001167623.2	c.3G>T	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>T	p.Met1?	start_lost	1/47	5	NM_001167623.2
CACNA1C	ENST00000399655.6	c.3G>T	p.Met1?	start_lost	1/47	1	NM_000719.7

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445040 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 717176

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: 9.06e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

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

Invitae

Oct 22, 2023

This sequence change affects the initiator methionine of the CACNA1C mRNA. The next in-frame methionine is located at codon 8. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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	0.63	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Uncertain	24
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	0.95	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;