12-2674571-G-A

Position:

• chr12-2674571-G-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.4757G>A​(p.Arg1586Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000282 in 1,419,920 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: 33)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CACNA1C NM_000719.7 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• 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 (HGNC:):

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). GenCC has associacion of 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, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7	c.4757G>A	p.Arg1586Gln	missense_variant	39/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2	c.4757G>A	p.Arg1586Gln	missense_variant	39/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6	c.4757G>A	p.Arg1586Gln	missense_variant	39/47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6	c.4757G>A	p.Arg1586Gln	missense_variant	39/47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1	c.4991G>A	p.Arg1664Gln	missense_variant	41/50			ENSP00000507184.1
CACNA1C	ENST00000406454.8	c.4757G>A	p.Arg1586Gln	missense_variant	39/48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6	c.4724G>A	p.Arg1575Gln	missense_variant	38/47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1	c.4922G>A	p.Arg1641Gln	missense_variant	40/48			ENSP00000507867.1
CACNA1C	ENST00000347598.9	c.4901G>A	p.Arg1634Gln	missense_variant	41/49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7	c.4880G>A	p.Arg1627Gln	missense_variant	39/47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12	c.4757G>A	p.Arg1586Gln	missense_variant	39/48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6	c.4757G>A	p.Arg1586Gln	missense_variant	39/48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1	c.4847G>A	p.Arg1616Gln	missense_variant	39/47			ENSP00000507105.1
CACNA1C	ENST00000683781.1	c.4847G>A	p.Arg1616Gln	missense_variant	39/47			ENSP00000507434.1
CACNA1C	ENST00000683840.1	c.4847G>A	p.Arg1616Gln	missense_variant	39/47			ENSP00000507612.1
CACNA1C	ENST00000683956.1	c.4847G>A	p.Arg1616Gln	missense_variant	39/47			ENSP00000506882.1
CACNA1C	ENST00000399638.5	c.4841G>A	p.Arg1614Gln	missense_variant	40/48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10	c.4832G>A	p.Arg1611Gln	missense_variant	40/48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5	c.4817G>A	p.Arg1606Gln	missense_variant	40/48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5	c.4814G>A	p.Arg1605Gln	missense_variant	39/47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5	c.4814G>A	p.Arg1605Gln	missense_variant	39/47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7	c.4814G>A	p.Arg1605Gln	missense_variant	39/47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5	c.4808G>A	p.Arg1603Gln	missense_variant	39/47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1	c.4799G>A	p.Arg1600Gln	missense_variant	39/47			ENSP00000507898.1
CACNA1C	ENST00000399591.5	c.4781G>A	p.Arg1594Gln	missense_variant	38/46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5	c.4781G>A	p.Arg1594Gln	missense_variant	38/46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5	c.4775G>A	p.Arg1592Gln	missense_variant	38/46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5	c.4757G>A	p.Arg1586Gln	missense_variant	39/47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5	c.4757G>A	p.Arg1586Gln	missense_variant	39/47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6	c.4757G>A	p.Arg1586Gln	missense_variant	39/47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5	c.4757G>A	p.Arg1586Gln	missense_variant	39/47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1	c.4757G>A	p.Arg1586Gln	missense_variant	39/47			ENSP00000507282.1
CACNA1C	ENST00000683482.1	c.4748G>A	p.Arg1583Gln	missense_variant	39/47			ENSP00000507169.1
CACNA1C	ENST00000682686.1	c.4724G>A	p.Arg1575Gln	missense_variant	38/46			ENSP00000507309.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000528 AC: 1 AN: 189468 Hom.: 0 AF XY: 0.00000994 AC XY: 1 AN XY: 100592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000282 AC: 4 AN: 1419920 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 702150

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: 0.00000367

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00000833 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Long QT syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 17, 2021

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. 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. This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces arginine with glutamine at codon 1586 of the CACNA1C protein (p.Arg1586Gln). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and glutamine. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 03, 2024

The p.R1586Q variant (also known as c.4757G>A), located in coding exon 39 of the CACNA1C gene, results from a G to A substitution at nucleotide position 4757. The arginine at codon 1586 is replaced by glutamine, an amino acid with highly similar properties. This variant has been reported in a long QT syndrome cohort (Wemhöner K et al. J Mol Cell Cardiol, 2015 Mar;80:186-95). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.096	T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;T;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.88	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	2.5	.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.8	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	0.0010	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.
Sift4G	Benign	0.063	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;D;D
Polyphen		1.0, 0.50, 0.64, 0.086, 0.10, 1.0, 0.99, 0.99, 0.059, 0.17, 0.0080	.;D;D;P;P;B;B;D;D;D;B;B;D;B;B;.;B;B;.;.;.;B;.
Vest4		0.69
MVP		0.89
MPC		2.4
ClinPred		0.99	D
GERP RS		4.4
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

LitVar

Other links and lift over

dbSNP: rs375656252; hg19: chr12-2783737;