rs776318939

Variant names:

Variant summary

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

The NM_000719.7(CACNA1C):c.3391G>A(p.Asp1131Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,138 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D1131D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.70

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 12-2608545-G-A is Benign according to our data. Variant chr12-2608545-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456964.

BS2

High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.3541G>A	p.Asp1181Asn	missense_variant	Exon 28 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.3556G>A	p.Asp1186Asn	missense_variant	Exon 28 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.3451G>A	p.Asp1151Asn	missense_variant	Exon 28 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.3481G>A	p.Asp1161Asn	missense_variant	Exon 27 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.3481G>A	p.Asp1161Asn	missense_variant	Exon 27 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.3481G>A	p.Asp1161Asn	missense_variant	Exon 27 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.3481G>A	p.Asp1161Asn	missense_variant	Exon 27 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.3466G>A	p.Asp1156Asn	missense_variant	Exon 28 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.3451G>A	p.Asp1151Asn	missense_variant	Exon 28 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.3466G>A	p.Asp1156Asn	missense_variant	Exon 28 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.3382G>A	p.Asp1128Asn	missense_variant	Exon 27 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.3391G>A	p.Asp1131Asn	missense_variant	Exon 27 of 46			ENSP00000507309.1
CACNA1C	ENST00000480911.6 link	n.*1998G>A		non_coding_transcript_exon_variant	Exon 25 of 27	5		ENSP00000437936.2
CACNA1C	ENST00000480911.6 link	n.*1998G>A		3_prime_UTR_variant	Exon 25 of 27	5		ENSP00000437936.2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.0000321

AC:

AN:

249332

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000233

Gnomad ASJ exome

AF:

0.00

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:

0.00000548

AC:

AN:

1460912

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726642

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33462

American (AMR)

AF:

0.000179

AC:

AN:

44588

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86054

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111550

Other (OTH)

AF:

0.00

AC:

AN:

60368

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

AF:

0.00000657

AC:

AN:

152226

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74366

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68046

Other (OTH)

AF:

0.000478

AC:

AN:

2094

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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ventricular tachycardia

Uncertain:1

Mar 04, 2019

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Aug 20, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Oct 06, 2023

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

0.25

CardioboostArm

Benign

0.00031

BayesDel_addAF

Benign

-0.091

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

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

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.49

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

MetaSVM

Uncertain

0.79

MutationAssessor

Benign

0.89

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

PhyloP100

7.7

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.91

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

REVEL

Uncertain

0.57

Sift

Benign

0.43

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

0.66

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

Polyphen

1.0, 1.0, 0.33, 0.0030, 0.15, 0.088, 1.0, 0.91

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

Vest4

0.82

MutPred

0.54

.;.;.;.;.;.;.;.;.;.;.;Gain of catalytic residue at I1155 (P = 0.0049);Gain of catalytic residue at I1155 (P = 0.0049);.;.;.;.;.;.;.;.;.;.;.;

MVP

0.79

MPC

1.1

ClinPred

0.29

GERP RS

4.7

gMVP

0.95

Mutation Taster

=28/72

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over