12-2504854-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_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).

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

Publications

2 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 Gene-Disease associations (from GenCC):

Timothy syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
long QT syndrome
Inheritance: AD Classification: MODERATE Submitted by: ClinGen
long QT syndrome 8
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
Brugada syndrome
Inheritance: AD Classification: SUPPORTIVE, NO_KNOWN Submitted by: Orphanet, ClinGen
Brugada syndrome 3
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
intellectual disability
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
short QT syndrome
Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, ClinGen

CACNA1C links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

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 VariationId is 574774.

BS2

High AC in GnomAdExome4 at 80 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 47	ENST00000399655.6	NP_000710.5	Q13936-12
CACNA1C	NM_001167623.2 link	c.1217+315G>A		intron_variant	Intron 8 of 46	ENST00000399603.6	NP_001161095.1	Q13936-37

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CACNA1C	ENST00000399655.6 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 47	1	NM_000719.7	ENSP00000382563.1	Q13936-12
CACNA1C	ENST00000682544.1 link	c.1216G>A	p.Val406Ile	missense_variant	Exon 8 of 50			ENSP00000507184.1	A0A804HIR0
CACNA1C	ENST00000347598.9 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 49	1		ENSP00000266376.6	Q13936-11
CACNA1C	ENST00000344100.7 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 47	1		ENSP00000341092.3	Q13936-14
CACNA1C	ENST00000327702.12 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 48	1		ENSP00000329877.7	A0A0A0MR67
CACNA1C	ENST00000399638.5 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 48	1		ENSP00000382547.1	Q13936-31
CACNA1C	ENST00000335762.10 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 48	5		ENSP00000336982.5	F5H522
CACNA1C	ENST00000399606.5 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 48	1		ENSP00000382515.1	Q13936-30
CACNA1C	ENST00000399621.5 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 47	1		ENSP00000382530.1	Q13936-24
CACNA1C	ENST00000399637.5 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 47	1		ENSP00000382546.1	Q13936-27
CACNA1C	ENST00000402845.7 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 47	1		ENSP00000385724.3	Q13936-13
CACNA1C	ENST00000399629.5 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 47	1		ENSP00000382537.1	Q13936-32
CACNA1C	ENST00000682336.1 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 47			ENSP00000507898.1	A0A804HKE9
CACNA1C	ENST00000399591.5 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 46	1		ENSP00000382500.1	Q13936-29
CACNA1C	ENST00000399595.5 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 46	1		ENSP00000382504.1	Q13936-25
CACNA1C	ENST00000399649.5 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 46	1		ENSP00000382557.1	Q13936-15
CACNA1C	ENST00000399597.5 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 47	1		ENSP00000382506.1	Q13936-22
CACNA1C	ENST00000399601.5 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 47	1		ENSP00000382510.1	Q13936-20
CACNA1C	ENST00000399644.5 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 47	1		ENSP00000382552.1	Q13936-21
CACNA1C	ENST00000683482.1 link	c.1117G>A	p.Val373Ile	missense_variant	Exon 8 of 47			ENSP00000507169.1	Q13936-35
CACNA1C	ENST00000682686.1 link	c.1126G>A	p.Val376Ile	missense_variant	Exon 8 of 46			ENSP00000507309.1	Q13936-19
CACNA1C	ENST00000399603.6 link	c.1217+315G>A		intron_variant	Intron 8 of 46	5	NM_001167623.2	ENSP00000382512.1	Q13936-37
CACNA1C	ENST00000406454.8 link	c.1217+315G>A		intron_variant	Intron 8 of 47	5		ENSP00000385896.3	F5GY28
CACNA1C	ENST00000399634.6 link	c.1217+315G>A		intron_variant	Intron 8 of 46	5		ENSP00000382542.2	E9PDI6
CACNA1C	ENST00000683824.1 link	c.1307+315G>A		intron_variant	Intron 8 of 47			ENSP00000507867.1	A0A804HKC4
CACNA1C	ENST00000399617.6 link	c.1217+315G>A		intron_variant	Intron 8 of 47	5		ENSP00000382526.1	A0A0A0MSA1
CACNA1C	ENST00000682462.1 link	c.1307+315G>A		intron_variant	Intron 8 of 46			ENSP00000507105.1	A0A804HIJ8
CACNA1C	ENST00000683781.1 link	c.1307+315G>A		intron_variant	Intron 8 of 46			ENSP00000507434.1	A0A804HJB6
CACNA1C	ENST00000683840.1 link	c.1307+315G>A		intron_variant	Intron 8 of 46			ENSP00000507612.1	A0A804HJR1
CACNA1C	ENST00000683956.1 link	c.1307+315G>A		intron_variant	Intron 8 of 46			ENSP00000506882.1	A0A804HI37
CACNA1C	ENST00000399641.6 link	c.1217+315G>A		intron_variant	Intron 8 of 46	1		ENSP00000382549.1	Q13936-23
CACNA1C	ENST00000682835.1 link	c.1217+315G>A		intron_variant	Intron 8 of 46			ENSP00000507282.1	A0A804HIZ0
CACNA1C	ENST00000480911.6 link	n.1113+11468G>A		intron_variant	Intron 7 of 26	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

GnomAD2 exomes

AF:

0.0000362

AC:

AN:

248536

AF XY:

0.0000297

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 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

African (AFR)

AF:

0.00

AC:

AN:

32856

American (AMR)

AF:

0.0000224

AC:

AN:

44668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25928

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39548

South Asian (SAS)

AF:

0.0000468

AC:

AN:

85510

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53390

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5720

European-Non Finnish (NFE)

AF:

0.0000637

AC:

AN:

1083894

Other (OTH)

AF:

0.0000843

AC:

AN:

59288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.431

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

AF:

0.0000263

AC:

AN:

152064

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41482

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.000208

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67994

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

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

Oct 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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

Oct 22, 2019

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Jun 24, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

AlphaMissense

Benign

0.068

CardioboostArm

Benign

0.0000030

BayesDel_addAF

Benign

-0.0062

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

(source)

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

PhyloP100

4.9

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

PromoterAI

0.0021

Neutral

(source)

gMVP

0.73

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over