rs1131653

Positions:

chr12-2504854-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_000719.7(CACNA1C):c.1126G>A(p.Val376Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000531 in 1,582,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V376L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 4.86

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.09785399).

BP6

Variant 12-2504854-G-A is Benign according to our data. Variant chr12-2504854-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 574774.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.

BS2

High AC in GnomAdExome4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 linkuse as main transcript	c.1217+315G>A		intron_variant		ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 linkuse as main transcript	c.1216G>A	p.Val406Ile	missense_variant	8/50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000347598.9 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399638.5 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399644.5 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000683482.1 linkuse as main transcript	c.1117G>A	p.Val373Ile	missense_variant	8/47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	8/46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.1217+315G>A		intron_variant		5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000406454.8 linkuse as main transcript	c.1217+315G>A		intron_variant		5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 linkuse as main transcript	c.1217+315G>A		intron_variant		5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 linkuse as main transcript	c.1307+315G>A		intron_variant				ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000399617.6 linkuse as main transcript	c.1217+315G>A		intron_variant		5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 linkuse as main transcript	c.1307+315G>A		intron_variant				ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 linkuse as main transcript	c.1307+315G>A		intron_variant				ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 linkuse as main transcript	c.1307+315G>A		intron_variant				ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 linkuse as main transcript	c.1307+315G>A		intron_variant				ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399641.6 linkuse as main transcript	c.1217+315G>A		intron_variant		1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000682835.1 linkuse as main transcript	c.1217+315G>A		intron_variant				ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000480911.6 linkuse as main transcript	n.1113+11468G>A		intron_variant		5		ENSP00000437936.2	F5H638

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

151946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000362

AC:

AN:

248536

Hom.:

AF XY:

0.0000297

AC XY:

AN XY:

134870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000559

AC:

AN:

1430802

Hom.:

Cov.:

AF XY:

0.0000462

AC XY:

AN XY:

713982

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0000468

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000637

Gnomad4 OTH exome

AF:

0.0000843

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74344

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.0000453

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000331

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 20, 2024

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 376 of the CACNA1C protein (p.Val376Ile). This variant is present in population databases (rs1131653, gnomAD 0.01%). 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: 574774). 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 not expected to disrupt CACNA1C protein function with a negative 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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Oct 22, 2019

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 24, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.0062

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Benign

0.83

DEOGEN2

Benign

0.31

T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.85

M_CAP

Benign

0.051

MetaRNN

Benign

0.098

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.28

MutationAssessor

Benign

0.22

.;N;.;N;N;N;N;N;N;N;N;N;N;N;N;.;N;N

PrimateAI

Uncertain

0.65

PROVEAN

Benign

0.080

N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N;N

REVEL

Uncertain

0.43

Sift

Benign

0.62

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Sift4G

Benign

0.75

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T

Polyphen

0.0010, 0.0, 0.26

.;B;.;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B

Vest4

0.27

MVP

0.88

MPC

0.86

ClinPred

0.048

GERP RS

4.3

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over