rs773930851

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.5023G>A(p.Ala1675Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000818 in 1,613,850 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 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: 9.27

Publications

4 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17867368).

BP6

Variant 12-2677799-G-A is Benign according to our data. Variant chr12-2677799-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 308159.

BS2

High AC in GnomAdExome4 at 130 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.5023G>A	p.Ala1675Thr	missense_variant	Exon 41 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.5023G>A	p.Ala1675Thr	missense_variant	Exon 41 of 47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CACNA1C	ENST00000399603.6 link	c.5023G>A	p.Ala1675Thr	missense_variant	Exon 41 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.5023G>A	p.Ala1675Thr	missense_variant	Exon 41 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.5257G>A	p.Ala1753Thr	missense_variant	Exon 43 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.5023G>A	p.Ala1675Thr	missense_variant	Exon 41 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.4990G>A	p.Ala1664Thr	missense_variant	Exon 40 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.5188G>A	p.Ala1730Thr	missense_variant	Exon 42 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.5167G>A	p.Ala1723Thr	missense_variant	Exon 43 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.5146G>A	p.Ala1716Thr	missense_variant	Exon 41 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.5023G>A	p.Ala1675Thr	missense_variant	Exon 41 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.5023G>A	p.Ala1675Thr	missense_variant	Exon 41 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.5113G>A	p.Ala1705Thr	missense_variant	Exon 41 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.5113G>A	p.Ala1705Thr	missense_variant	Exon 41 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.5113G>A	p.Ala1705Thr	missense_variant	Exon 41 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.5113G>A	p.Ala1705Thr	missense_variant	Exon 41 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.5107G>A	p.Ala1703Thr	missense_variant	Exon 42 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.5098G>A	p.Ala1700Thr	missense_variant	Exon 42 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.5083G>A	p.Ala1695Thr	missense_variant	Exon 42 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.5080G>A	p.Ala1694Thr	missense_variant	Exon 41 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.5080G>A	p.Ala1694Thr	missense_variant	Exon 41 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.5080G>A	p.Ala1694Thr	missense_variant	Exon 41 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.5074G>A	p.Ala1692Thr	missense_variant	Exon 41 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.5065G>A	p.Ala1689Thr	missense_variant	Exon 41 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.5047G>A	p.Ala1683Thr	missense_variant	Exon 40 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.5047G>A	p.Ala1683Thr	missense_variant	Exon 40 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.5041G>A	p.Ala1681Thr	missense_variant	Exon 40 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.5023G>A	p.Ala1675Thr	missense_variant	Exon 41 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.5023G>A	p.Ala1675Thr	missense_variant	Exon 41 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.5023G>A	p.Ala1675Thr	missense_variant	Exon 41 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.5023G>A	p.Ala1675Thr	missense_variant	Exon 41 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.5023G>A	p.Ala1675Thr	missense_variant	Exon 41 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.5014G>A	p.Ala1672Thr	missense_variant	Exon 41 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.4990G>A	p.Ala1664Thr	missense_variant	Exon 40 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152198

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000104

AC:

AN:

249200

AF XY:

0.0000814

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000221

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.0000889

AC:

130

AN:

1461652

Hom.:

Cov.:

AF XY:

0.0000839

AC XY:

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000348

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000971

AC:

108

AN:

1111840

Other (OTH)

AF:

0.000265

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

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:

0.0000131

AC:

AN:

152198

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41444

American (AMR)

AF:

0.00

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68036

Other (OTH)

AF:

0.00

AC:

AN:

2094

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

Alfa

AF:

0.000135

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.000182

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Timothy syndrome

Uncertain:1

Apr 23, 2018

Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Long QT syndrome

Benign:1

Dec 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Apr 04, 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

Uncertain

0.45

CardioboostArm

Benign

0.000047

BayesDel_addAF

Benign

-0.083

BayesDel_noAF

Uncertain

-0.070

CADD

Uncertain

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.0099

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

Eigen

Benign

0.0054

Eigen_PC

Benign

-0.0043

FATHMM_MKL

Pathogenic

1.0

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.18

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

0.19

MutationAssessor

Uncertain

2.4

.;.;.;.;.;.;.;.;.;.;M;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

9.3

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.2

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

REVEL

Uncertain

0.33

Sift

Benign

0.36

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

Sift4G

Benign

0.56

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

Polyphen

0.91, 0.22, 0.031, 0.33, 0.85, 0.97, 0.19, 0.94, 0.93, 0.99, 0.97

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

Vest4

0.38

MVP

0.85

MPC

0.20

ClinPred

0.25

GERP RS

4.6

gMVP

0.55

Mutation Taster

=56/44

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over