rs552478740

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000719.7(CACNA1C):c.6001G>A(p.Gly2001Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,613,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.08

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:

CACNA1C-AS1 (HGNC:40119): (CACNA1C antisense RNA 1)

CACNA1C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06362143).

BP6

Variant 12-2688663-G-A is Benign according to our data. Variant chr12-2688663-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 575699.

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.6001G>A	p.Gly2001Ser	missense_variant	Exon 46 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.6001G>A	p.Gly2001Ser	missense_variant	Exon 46 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.6001G>A	p.Gly2001Ser	missense_variant	Exon 46 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.6001G>A	p.Gly2001Ser	missense_variant	Exon 46 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.6340G>A	p.Gly2114Ser	missense_variant	Exon 49 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.6214G>A	p.Gly2072Ser	missense_variant	Exon 47 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.6181G>A	p.Gly2061Ser	missense_variant	Exon 46 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.6166G>A	p.Gly2056Ser	missense_variant	Exon 47 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.6145G>A	p.Gly2049Ser	missense_variant	Exon 48 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.6124G>A	p.Gly2042Ser	missense_variant	Exon 46 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.6106G>A	p.Gly2036Ser	missense_variant	Exon 47 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.6106G>A	p.Gly2036Ser	missense_variant	Exon 47 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.6091G>A	p.Gly2031Ser	missense_variant	Exon 46 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.6091G>A	p.Gly2031Ser	missense_variant	Exon 46 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.6091G>A	p.Gly2031Ser	missense_variant	Exon 46 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.6091G>A	p.Gly2031Ser	missense_variant	Exon 46 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.6085G>A	p.Gly2029Ser	missense_variant	Exon 47 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.6076G>A	p.Gly2026Ser	missense_variant	Exon 47 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.6061G>A	p.Gly2021Ser	missense_variant	Exon 47 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.6058G>A	p.Gly2020Ser	missense_variant	Exon 46 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.6058G>A	p.Gly2020Ser	missense_variant	Exon 46 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.6058G>A	p.Gly2020Ser	missense_variant	Exon 46 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.6052G>A	p.Gly2018Ser	missense_variant	Exon 46 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.6043G>A	p.Gly2015Ser	missense_variant	Exon 46 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.6025G>A	p.Gly2009Ser	missense_variant	Exon 45 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.6025G>A	p.Gly2009Ser	missense_variant	Exon 45 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.6019G>A	p.Gly2007Ser	missense_variant	Exon 45 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.6001G>A	p.Gly2001Ser	missense_variant	Exon 46 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.6001G>A	p.Gly2001Ser	missense_variant	Exon 46 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.6001G>A	p.Gly2001Ser	missense_variant	Exon 46 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.6001G>A	p.Gly2001Ser	missense_variant	Exon 46 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.6001G>A	p.Gly2001Ser	missense_variant	Exon 46 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.5992G>A	p.Gly1998Ser	missense_variant	Exon 46 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.5968G>A	p.Gly1990Ser	missense_variant	Exon 45 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000566

AC:

AN:

247140

AF XY:

0.0000818

show subpopulations

Gnomad AFR exome

AF:

0.000132

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000112

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000716

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000342

AC:

AN:

1461296

Hom.:

Cov.:

AF XY:

0.0000385

AC XY:

AN XY:

726976

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33474

American (AMR)

AF:

0.0000224

AC:

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.000101

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86242

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53164

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000324

AC:

AN:

1111778

Other (OTH)

AF:

0.0000166

AC:

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

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:

0.0000394

AC:

AN:

152308

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41560

American (AMR)

AF:

0.00

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

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:

0.00

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000580

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Timothy syndrome;C2678478:Brugada syndrome 3

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Sep 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Dec 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

May 30, 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

0.074

CardioboostArm

Benign

0.0000020

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.017

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

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.085

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.064

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

-0.26

PhyloP100

1.1

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.30

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

REVEL

Benign

0.27

Sift

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;.

Sift4G

Benign

0.27

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

Polyphen

0.0, 0.0010, 0.26, 0.16, 0.43, 0.041

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

Vest4

0.20

MVP

0.43

MPC

0.19

ClinPred

0.013

GERP RS

0.97

gMVP

0.32

Mutation Taster

=87/13

polymorphism

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over