12-2605088-G-C

Position:

• chr12-2605088-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_000719.7(CACNA1C):​c.2968G>C​(p.Ala990Pro) 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CACNA1C NM_000719.7 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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• 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). The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 91 curated benign missense variants. GenCC has associacion of the 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.88

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.2968G>C	p.Ala990Pro	missense_variant	23/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.2968G>C	p.Ala990Pro	missense_variant	23/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.2968G>C	p.Ala990Pro	missense_variant	23/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.2968G>C	p.Ala990Pro	missense_variant	23/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.3118G>C	p.Ala1040Pro	missense_variant	24/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.2968G>C	p.Ala990Pro	missense_variant	23/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.2968G>C	p.Ala990Pro	missense_variant	23/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.3133G>C	p.Ala1045Pro	missense_variant	24/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.3028G>C	p.Ala1010Pro	missense_variant	24/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.2968G>C	p.Ala990Pro	missense_variant	23/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.2968G>C	p.Ala990Pro	missense_variant	23/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.2968G>C	p.Ala990Pro	missense_variant	23/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.3058G>C	p.Ala1020Pro	missense_variant	23/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.3058G>C	p.Ala1020Pro	missense_variant	23/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.3058G>C	p.Ala1020Pro	missense_variant	23/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.3058G>C	p.Ala1020Pro	missense_variant	23/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.2968G>C	p.Ala990Pro	missense_variant	23/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.3043G>C	p.Ala1015Pro	missense_variant	24/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.3028G>C	p.Ala1010Pro	missense_variant	24/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.2968G>C	p.Ala990Pro	missense_variant	23/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.2968G>C	p.Ala990Pro	missense_variant	23/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.2968G>C	p.Ala990Pro	missense_variant	23/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.2968G>C	p.Ala990Pro	missense_variant	23/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.3043G>C	p.Ala1015Pro	missense_variant	24/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.2968G>C	p.Ala990Pro	missense_variant	23/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.2968G>C	p.Ala990Pro	missense_variant	23/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.2968G>C	p.Ala990Pro	missense_variant	23/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.2968G>C	p.Ala990Pro	missense_variant	23/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.2968G>C	p.Ala990Pro	missense_variant	23/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.2968G>C	p.Ala990Pro	missense_variant	23/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.2968G>C	p.Ala990Pro	missense_variant	23/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.2968G>C	p.Ala990Pro	missense_variant	23/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.2959G>C	p.Ala987Pro	missense_variant	23/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.2968G>C	p.Ala990Pro	missense_variant	23/46			ENSP00000507309.1
CACNA1C	ENST00000480911.6	n.*1575G>C		non_coding_transcript_exon_variant	21/27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6	n.*1575G>C		3_prime_UTR_variant	21/27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 24, 2023

The p.A990P variant (also known as c.2968G>C), located in coding exon 23 of the CACNA1C gene, results from a G to C substitution at nucleotide position 2968. The alanine at codon 990 is replaced by proline, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.88	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	2.3	.;.;.;.;.;.;.;.;.;.;.;M;M;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.8	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	0.90
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	0.026	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, 1.0, 0.71, 1.0, 0.82	.;D;D;P;D;D;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;D
Vest4		0.81
MutPred		0.58		.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at Q1007 (P = 0.0112);Gain of catalytic residue at Q1007 (P = 0.0112);.;.;.;.;.;.;.;.;.;.;
MVP		0.96
MPC		1.6
ClinPred		0.99	D
GERP RS		4.5
gMVP		0.99

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: chr12-2714254;