12-2605097-G-C

Variant names:

• chr12-2605097-G-C
• rs1555878893
• NM_000719.7:c.2977G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3 PP5_Moderate

The NM_000719.7(CACNA1C):​c.2977G>C​(p.Val993Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P: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]

CACNA1C-AS3 (HGNC:40117): (CACNA1C antisense RNA 3)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the CACNA1C gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. Gene score misZ: 6.4654 (above the threshold of 3.09). Trascript score misZ: 7.2674 (above the threshold of 3.09). GenCC associations: The gene is linked to 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.806
• PP5: Variant 12-2605097-G-C is Pathogenic according to our data. Variant chr12-2605097-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 450908.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3127G>C	p.Val1043Leu	missense_variant	Exon 24 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3142G>C	p.Val1048Leu	missense_variant	Exon 24 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3037G>C	p.Val1013Leu	missense_variant	Exon 24 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3067G>C	p.Val1023Leu	missense_variant	Exon 23 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3067G>C	p.Val1023Leu	missense_variant	Exon 23 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3067G>C	p.Val1023Leu	missense_variant	Exon 23 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3067G>C	p.Val1023Leu	missense_variant	Exon 23 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3052G>C	p.Val1018Leu	missense_variant	Exon 24 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3037G>C	p.Val1013Leu	missense_variant	Exon 24 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3052G>C	p.Val1018Leu	missense_variant	Exon 24 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2968G>C	p.Val990Leu	missense_variant	Exon 23 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2977G>C	p.Val993Leu	missense_variant	Exon 23 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1584G>C		non_coding_transcript_exon_variant	Exon 21 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1584G>C		3_prime_UTR_variant	Exon 21 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Aug 03, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on 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	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.75
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.81	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	Uncertain	2.4	.;.;.;.;.;.;.;.;.;.;.;M;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.9	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.013	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.028	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 0.90, 0.89, 0.98, 1.0, 1.0, 1.0, 0.96, 0.98, 0.96	.;D;P;P;D;D;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.70
MutPred		0.48		.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at A1010 (P = 0.0023);Gain of catalytic residue at A1010 (P = 0.0023);.;.;.;.;.;.;.;.;.;.;
MVP		0.95
MPC		1.5
ClinPred		0.98	D
GERP RS		4.5
gMVP		0.97

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: rs1555878893; hg19: chr12-2714263;