12-2688778-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_000719.7(CACNA1C):c.6116C>G(p.Ala2039Gly) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000856 in 1,518,952 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. A2039V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000089 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense, splice_region

Scores

Splicing: ADA: 0.9754

Clinical Significance

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

Conservation

PhyloP100: 5.71

Publications

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

BP4

Computational evidence support a benign effect (MetaRNN=0.33257252).

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CACNA1C	NM_000719.7 link	c.6116C>G	p.Ala2039Gly	missense_variant, splice_region_variant	Exon 46 of 47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 link	c.6116C>G	p.Ala2039Gly	missense_variant, splice_region_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.6116C>G	p.Ala2039Gly	missense_variant, splice_region_variant	Exon 46 of 47	5	NM_001167623.2	ENSP00000382512.1
CACNA1C	ENST00000399655.6 link	c.6116C>G	p.Ala2039Gly	missense_variant, splice_region_variant	Exon 46 of 47	1	NM_000719.7	ENSP00000382563.1
CACNA1C	ENST00000682544.1 link	c.6455C>G	p.Ala2152Gly	missense_variant, splice_region_variant	Exon 49 of 50			ENSP00000507184.1
CACNA1C	ENST00000406454.8 link	c.6329C>G	p.Ala2110Gly	missense_variant, splice_region_variant	Exon 47 of 48	5		ENSP00000385896.3
CACNA1C	ENST00000399634.6 link	c.6296C>G	p.Ala2099Gly	missense_variant, splice_region_variant	Exon 46 of 47	5		ENSP00000382542.2
CACNA1C	ENST00000683824.1 link	c.6281C>G	p.Ala2094Gly	missense_variant, splice_region_variant	Exon 47 of 48			ENSP00000507867.1
CACNA1C	ENST00000347598.9 link	c.6260C>G	p.Ala2087Gly	missense_variant, splice_region_variant	Exon 48 of 49	1		ENSP00000266376.6
CACNA1C	ENST00000344100.7 link	c.6239C>G	p.Ala2080Gly	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000341092.3
CACNA1C	ENST00000327702.12 link	c.6221C>G	p.Ala2074Gly	missense_variant, splice_region_variant	Exon 47 of 48	1		ENSP00000329877.7
CACNA1C	ENST00000399617.6 link	c.6221C>G	p.Ala2074Gly	missense_variant, splice_region_variant	Exon 47 of 48	5		ENSP00000382526.1
CACNA1C	ENST00000682462.1 link	c.6206C>G	p.Ala2069Gly	missense_variant, splice_region_variant	Exon 46 of 47			ENSP00000507105.1
CACNA1C	ENST00000683781.1 link	c.6206C>G	p.Ala2069Gly	missense_variant, splice_region_variant	Exon 46 of 47			ENSP00000507434.1
CACNA1C	ENST00000683840.1 link	c.6206C>G	p.Ala2069Gly	missense_variant, splice_region_variant	Exon 46 of 47			ENSP00000507612.1
CACNA1C	ENST00000683956.1 link	c.6206C>G	p.Ala2069Gly	missense_variant, splice_region_variant	Exon 46 of 47			ENSP00000506882.1
CACNA1C	ENST00000399638.5 link	c.6200C>G	p.Ala2067Gly	missense_variant, splice_region_variant	Exon 47 of 48	1		ENSP00000382547.1
CACNA1C	ENST00000335762.10 link	c.6191C>G	p.Ala2064Gly	missense_variant, splice_region_variant	Exon 47 of 48	5		ENSP00000336982.5
CACNA1C	ENST00000399606.5 link	c.6176C>G	p.Ala2059Gly	missense_variant, splice_region_variant	Exon 47 of 48	1		ENSP00000382515.1
CACNA1C	ENST00000399621.5 link	c.6173C>G	p.Ala2058Gly	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000382530.1
CACNA1C	ENST00000399637.5 link	c.6173C>G	p.Ala2058Gly	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000382546.1
CACNA1C	ENST00000402845.7 link	c.6173C>G	p.Ala2058Gly	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000385724.3
CACNA1C	ENST00000399629.5 link	c.6167C>G	p.Ala2056Gly	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000382537.1
CACNA1C	ENST00000682336.1 link	c.6158C>G	p.Ala2053Gly	missense_variant, splice_region_variant	Exon 46 of 47			ENSP00000507898.1
CACNA1C	ENST00000399591.5 link	c.6140C>G	p.Ala2047Gly	missense_variant, splice_region_variant	Exon 45 of 46	1		ENSP00000382500.1
CACNA1C	ENST00000399595.5 link	c.6140C>G	p.Ala2047Gly	missense_variant, splice_region_variant	Exon 45 of 46	1		ENSP00000382504.1
CACNA1C	ENST00000399649.5 link	c.6134C>G	p.Ala2045Gly	missense_variant, splice_region_variant	Exon 45 of 46	1		ENSP00000382557.1
CACNA1C	ENST00000399597.5 link	c.6116C>G	p.Ala2039Gly	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000382506.1
CACNA1C	ENST00000399601.5 link	c.6116C>G	p.Ala2039Gly	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000382510.1
CACNA1C	ENST00000399641.6 link	c.6116C>G	p.Ala2039Gly	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000382549.1
CACNA1C	ENST00000399644.5 link	c.6116C>G	p.Ala2039Gly	missense_variant, splice_region_variant	Exon 46 of 47	1		ENSP00000382552.1
CACNA1C	ENST00000682835.1 link	c.6116C>G	p.Ala2039Gly	missense_variant, splice_region_variant	Exon 46 of 47			ENSP00000507282.1
CACNA1C	ENST00000683482.1 link	c.6107C>G	p.Ala2036Gly	missense_variant, splice_region_variant	Exon 46 of 47			ENSP00000507169.1
CACNA1C	ENST00000682686.1 link	c.6083C>G	p.Ala2028Gly	missense_variant, splice_region_variant	Exon 45 of 46			ENSP00000507309.1

Frequencies

GnomAD3 genomes

AF:

0.0000592

AC:

AN:

152130

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000889

AC:

AN:

134984

AF XY:

0.0000415

show subpopulations

Gnomad AFR exome

AF:

0.000112

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000107

Gnomad NFE exome

AF:

0.000170

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000885

AC:

121

AN:

1366822

Hom.:

Cov.:

AF XY:

0.0000835

AC XY:

AN XY:

670856

show subpopulations

African (AFR)

AF:

0.0000321

AC:

AN:

31156

American (AMR)

AF:

0.00

AC:

AN:

33066

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21864

East Asian (EAS)

AF:

0.00

AC:

AN:

36868

South Asian (SAS)

AF:

0.00

AC:

AN:

73572

European-Finnish (FIN)

AF:

0.0000240

AC:

AN:

41652

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5426

European-Non Finnish (NFE)

AF:

0.000110

AC:

117

AN:

1066604

Other (OTH)

AF:

0.0000353

AC:

AN:

56614

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

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:

0.0000592

AC:

AN:

152130

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74304

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41438

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68014

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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:

0.0000340

ExAC

AF:

0.0000255

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Long QT syndrome 8

Uncertain:1

Feb 02, 2022

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with Long QT syndrome 8 (MIM #618447), and Timothy syndrome (MIM#601005). Missense variants result in loss of channel inactivation, and increased current (OMIM, PMID: 25260352). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from alanine to glycine. (I) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (12 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v3) (1 heterozygote, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated C-terminal domain (NCBI). (I) 0705 - No comparable missense variants have previous evidence for pathogenicity. (I) 0808 - Previous reports of pathogenicity for this variant are conflicting. This variant has been reported multiple times as a VUS in individuals with long QT or polymorphic catecholergic ventricular tachycardia (ClinVar) and in two individuals with unknown arrhythmia (PMID: 30847666). It has also been reported as a polymorphism in a LQT patient (PMID: 25633834). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1007 - No published functional evidence has been identified for this variant. (I) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign

Catecholaminergic polymorphic ventricular tachycardia

Uncertain:1

Dec 18, 2017

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

not provided

Uncertain:1

Jan 05, 2015

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Long QT syndrome

Uncertain:1

Jul 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 2039 of the CACNA1C protein (p.Ala2039Gly). This variant is present in population databases (rs549476254, gnomAD 0.02%). This missense change has been observed in individual(s) with CACNA1C-related conditions (PMID: 25633834, 30847666). ClinVar contains an entry for this variant (Variation ID: 197538). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. 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.

Cardiovascular phenotype

Benign:1

Sep 27, 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

Pathogenic

0.70

CardioboostArm

Benign

0.023

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.19

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.035

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

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

M_CAP

Benign

0.072

MetaRNN

Benign

0.33

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

-0.17

MutationAssessor

Benign

0.0

.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.

PhyloP100

5.7

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.

REVEL

Uncertain

0.35

Sift

Uncertain

0.0040

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.

Sift4G

Benign

0.063

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;T;T;D;D;D;D

Vest4

0.69

ClinPred

0.49

GERP RS

5.4

gMVP

0.62

Mutation Taster

=10/90

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Benign

0.67

SpliceAI score (max)

0.050

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