12-2053565-G-C

Variant names:

• chr12-2053565-G-C
• NM_000719.7:c.3G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting 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 Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 8 codons. Genomic position: 2053584. Lost 0.003 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.3G>C	p.Met1?	start_lost	Exon 1 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.3G>C	p.Met1?	start_lost	Exon 1 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.3G>C	p.Met1?	start_lost	Exon 1 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.3G>C	p.Met1?	start_lost	Exon 1 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000406454.8	c.3G>C	p.Met1?	start_lost	Exon 1 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.3G>C	p.Met1?	start_lost	Exon 1 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000347598.9	c.3G>C	p.Met1?	start_lost	Exon 1 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.3G>C	p.Met1?	start_lost	Exon 1 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.3G>C	p.Met1?	start_lost	Exon 1 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.3G>C	p.Met1?	start_lost	Exon 1 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000399638.5	c.3G>C	p.Met1?	start_lost	Exon 1 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3G>C	p.Met1?	start_lost	Exon 1 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3G>C	p.Met1?	start_lost	Exon 1 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.3G>C	p.Met1?	start_lost	Exon 1 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.3G>C	p.Met1?	start_lost	Exon 1 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.3G>C	p.Met1?	start_lost	Exon 1 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.3G>C	p.Met1?	start_lost	Exon 1 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3G>C	p.Met1?	start_lost	Exon 1 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.3G>C	p.Met1?	start_lost	Exon 1 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.3G>C	p.Met1?	start_lost	Exon 1 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.3G>C	p.Met1?	start_lost	Exon 1 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.3G>C	p.Met1?	start_lost	Exon 1 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.3G>C	p.Met1?	start_lost	Exon 1 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.3G>C	p.Met1?	start_lost	Exon 1 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.3G>C	p.Met1?	start_lost	Exon 1 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.3G>C	p.Met1?	start_lost	Exon 1 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.3G>C	p.Met1?	start_lost	Exon 1 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.3G>C	p.Met1?	start_lost	Exon 1 of 46			ENSP00000507309.1
CACNA1C	ENST00000682544.1	c.140-61659G>C		intron_variant	Intron 1 of 49			ENSP00000507184.1
CACNA1C	ENST00000683824.1	c.140-61659G>C		intron_variant	Intron 1 of 47			ENSP00000507867.1
CACNA1C	ENST00000682462.1	c.140-61659G>C		intron_variant	Intron 1 of 46			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.140-61659G>C		intron_variant	Intron 1 of 46			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.140-61659G>C		intron_variant	Intron 1 of 46			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.140-61659G>C		intron_variant	Intron 1 of 46			ENSP00000506882.1
CACNA1C	ENST00000480911.6	n.3G>C		non_coding_transcript_exon_variant	Exon 1 of 27	5		ENSP00000437936.2

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

Mar 05, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
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;