12-2668934-G-A

Variant names:

• chr12-2668934-G-A
• rs771053661
• NM_000719.7:c.4625G>A

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.4625G>A​(p.Arg1542His) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense, splice_region
• Scores: Splicing: ADA: 0.8058
• 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-AS2 (HGNC:):

CACNA1C-AS2 (HGNC:40118): (CACNA1C antisense RNA 2)

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 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, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4859G>A	p.Arg1620His	missense_variant, splice_region_variant	Exon 40 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4592G>A	p.Arg1531His	missense_variant, splice_region_variant	Exon 37 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4790G>A	p.Arg1597His	missense_variant, splice_region_variant	Exon 39 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4769G>A	p.Arg1590His	missense_variant, splice_region_variant	Exon 40 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4691G>A	p.Arg1564His	missense_variant, splice_region_variant	Exon 38 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4715G>A	p.Arg1572His	missense_variant, splice_region_variant	Exon 38 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4715G>A	p.Arg1572His	missense_variant, splice_region_variant	Exon 38 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4715G>A	p.Arg1572His	missense_variant, splice_region_variant	Exon 38 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4715G>A	p.Arg1572His	missense_variant, splice_region_variant	Exon 38 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4709G>A	p.Arg1570His	missense_variant, splice_region_variant	Exon 39 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4700G>A	p.Arg1567His	missense_variant, splice_region_variant	Exon 39 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4685G>A	p.Arg1562His	missense_variant, splice_region_variant	Exon 39 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4676G>A	p.Arg1559His	missense_variant, splice_region_variant	Exon 38 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4667G>A	p.Arg1556His	missense_variant, splice_region_variant	Exon 38 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4592G>A	p.Arg1531His	missense_variant, splice_region_variant	Exon 37 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4592G>A	p.Arg1531His	missense_variant, splice_region_variant	Exon 37 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4586G>A	p.Arg1529His	missense_variant, splice_region_variant	Exon 37 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4625G>A	p.Arg1542His	missense_variant, splice_region_variant	Exon 38 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4616G>A	p.Arg1539His	missense_variant, splice_region_variant	Exon 38 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4592G>A	p.Arg1531His	missense_variant, splice_region_variant	Exon 37 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250416 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135636

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459950 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 726442

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: 0.0000187

Gnomad4 NFE exome AF: 9.01e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Long QT syndrome Uncertain:1

Mar 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine with histidine at codon 1542 of the CACNA1C protein (p.Arg1542His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs771053661, ExAC no frequency). This variant has not been reported in the literature in individuals with CACNA1C-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.71	D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.92	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	2.5	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-4.6	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
REVEL	Pathogenic	0.87
Sift	Benign	0.031	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Uncertain	0.010	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, 0.75	.;D;D;P;D;D;D;D;D;D;D;D;D;D;D;.;D;D;.;.;.;D;.
Vest4		0.90
MutPred		0.66		.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at S1593 (P = 0);.;.;.;.;.;.;.;.;.;.;.;.;
MVP		0.94
MPC		2.5
ClinPred		1.0	D
GERP RS		3.7
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.81
dbscSNV1_RF	Pathogenic	0.81
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: rs771053661; hg19: chr12-2778100; COSMIC: COSV59749494;