chr12-2674571-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 10.0

Publications

3 publications found

Variant links:

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 links:

ITFG2-AS1 (HGNC:53128): (ITFG2 antisense RNA 1)

ITFG2-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.4757G>A	p.Arg1586Gln	missense_variant	Exon 39 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.4757G>A	p.Arg1586Gln	missense_variant	Exon 39 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

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

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000528

AC:

AN:

189468

AF XY:

0.00000994

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000282

AC:

AN:

1419920

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

702150

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32542

American (AMR)

AF:

0.00

AC:

AN:

38454

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25446

East Asian (EAS)

AF:

0.00

AC:

AN:

37546

South Asian (SAS)

AF:

0.00

AC:

AN:

80676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50476

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.00000367

AC:

AN:

1090196

Other (OTH)

AF:

0.00

AC:

AN:

58884

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00000833

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

May 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 1586 of the CACNA1C protein (p.Arg1586Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CACNA1C-related conditions. ClinVar contains an entry for this variant (Variation ID: 526921). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CACNA1C protein function with a positive predictive value of 95%. 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.

Cardiovascular phenotype

Uncertain:1

Jul 03, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

AlphaMissense

Pathogenic

0.81

CardioboostArm

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

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

LIST_S2

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

M_CAP

Pathogenic

0.88

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

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

PrimateAI

Pathogenic

0.83

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

Vest4

0.69

ClinPred

0.99

GERP RS

4.4

gMVP

0.99

Mutation Taster

=23/77

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over