rs369255950

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6BS2

The NM_000719.7(CACNA1C):c.1487G>A(p.Arg496Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000273 in 1,612,530 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R496W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 7.00

Publications

0 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: Likely_benign. The variant received -5 ACMG points.

BP6

Variant 12-2556956-G-A is Benign according to our data. Variant chr12-2556956-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 190640.

BS2

High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.1577G>A	p.Arg526Gln	missense_variant	Exon 11 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.1652G>A	p.Arg551Gln	missense_variant	Exon 12 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.1577G>A	p.Arg526Gln	missense_variant	Exon 11 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.1577G>A	p.Arg526Gln	missense_variant	Exon 11 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.1577G>A	p.Arg526Gln	missense_variant	Exon 11 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.1577G>A	p.Arg526Gln	missense_variant	Exon 11 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.1562G>A	p.Arg521Gln	missense_variant	Exon 12 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.1562G>A	p.Arg521Gln	missense_variant	Exon 12 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.1478G>A	p.Arg493Gln	missense_variant	Exon 11 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.1487G>A	p.Arg496Gln	missense_variant	Exon 11 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*94G>A		non_coding_transcript_exon_variant	Exon 9 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*94G>A		3_prime_UTR_variant	Exon 9 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152024

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000484

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000441

AC:

AN:

249244

AF XY:

0.0000592

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000556

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000260

AC:

AN:

1460506

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

726644

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39698

South Asian (SAS)

AF:

0.000232

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00000900

AC:

AN:

1110776

Other (OTH)

AF:

0.0000497

AC:

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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:

0.0000395

AC:

AN:

152024

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41348

American (AMR)

AF:

0.00

AC:

AN:

15266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.000208

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68018

Other (OTH)

AF:

0.00

AC:

AN:

2078

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

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:

0.000154

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.000520

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000496

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 03, 2017

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The R496Q variant of uncertain significance in the CACNA1C gene has not been published as pathogenic or benign to our knowledge. This variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). In addition, R496Q is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution also occurs at a position that is conserved across species. Furthermore, the majority of in silico algorithms predict R496Q is probably damaging to the protein structure/function. Therefore, additional evidence is needed to determine whether this variant is pathogenic or benign. -

Timothy syndrome;C2678478:Brugada syndrome 3;CN260585:Long qt syndrome 8

Uncertain:1

Aug 03, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Dec 01, 2023

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Mar 19, 2024

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as 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

0.31

CardioboostArm

Benign

0.0062

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.24

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.020

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

Eigen

Uncertain

0.53

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.11

MetaRNN

Uncertain

0.68

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.71

MutationAssessor

Benign

1.6

.;L;.;L;L;L;L;L;L;L;L;L;L;L;L;L;.;L;L;L;.;.;.

PhyloP100

7.0

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-1.4

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

REVEL

Pathogenic

0.72

Sift

Benign

0.11

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

Sift4G

Benign

0.13

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

Polyphen

0.98, 0.86, 0.073, 0.88, 0.94, 1.0, 0.99, 0.59, 0.99, 1.0, 1.0, 0.99, 0.99

.;D;P;B;P;P;D;D;D;P;D;D;D;D;D;D;.;D;D;.;.;.;D

Vest4

0.81

MVP

0.96

MPC

1.7

ClinPred

0.21

GERP RS

5.0

gMVP

0.87

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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