rs186867242

Positions:

chr12-2686232-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_000719.7(CACNA1C):c.5747A>G(p.Gln1916Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000169 in 1,613,314 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 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.70

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:

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

CACNA1C-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CACNA1C. . Gene score misZ 6.4654 (greater than the threshold 3.09). Trascript score misZ 7.2674 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, neurodevelopmental disorder with hypotonia, language delay, and skeletal defects with or without seizures, Brugada syndrome, long QT syndrome, short QT syndrome, long qt syndrome 8, Timothy syndrome, Brugada syndrome 3.

BP4

Computational evidence support a benign effect (MetaRNN=0.014277607).

BP6

Variant 12-2686232-A-G is Benign according to our data. Variant chr12-2686232-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 263515.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000164 (25/152356) while in subpopulation EAS AF= 0.00463 (24/5188). AF 95% confidence interval is 0.00319. There are 0 homozygotes in gnomad4. There are 12 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CACNA1C	NM_000719.7 linkuse as main transcript	c.5747A>G	p.Gln1916Arg	missense_variant	45/47	ENST00000399655.6
CACNA1C	NM_001167623.2 linkuse as main transcript	c.5747A>G	p.Gln1916Arg	missense_variant	45/47	ENST00000399603.6
CACNA1C-AS1	NR_045725.1 linkuse as main transcript	n.333+3908T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.5747A>G	p.Gln1916Arg	missense_variant	45/47	5	NM_001167623.2	Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.5747A>G	p.Gln1916Arg	missense_variant	45/47	1	NM_000719.7	Q13936-12
CACNA1C-AS1	ENST00000501371.5 linkuse as main transcript	n.294+3908T>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152238

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:

0.00462

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

GnomAD3 exomes

AF:

0.000221

AC:

AN:

249300

Hom.:

AF XY:

0.000222

AC XY:

AN XY:

135246

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00295

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000169

AC:

247

AN:

1460958

Hom.:

Cov.:

AF XY:

0.000165

AC XY:

120

AN XY:

726800

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00599

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.000164

AC:

AN:

152356

Hom.:

Cov.:

AF XY:

0.000161

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00463

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.000149

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 25, 2019

Variant summary: The variant, CACNA1C c.5747A>G (p.Gln1916Arg) results in a conservative amino acid change located in the Voltage-gated calcium channel subunit alpha, C-terminal domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00021 in 277978 control chromosomes, predominantly at a frequency of 0.0029 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 290 fold of the estimated maximal expected allele frequency for a pathogenic variant in CACNA1C causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. The variant, c.5747A>G has been reported in the literature in individuals affected with sudden cardiac death, sudden unexplained death syndrome and congenital long-QT syndrome (Liu_2017, Hata_2016, Chae_2017) including one large family study that showed incomplete penetrance for the variant. However, all these studies were of the same ethnic compoisition as seen in the control databases. Therefore, these reports do not provide unequivocal evidence supporting a deleterious outcome. Electrophysiological experiments using CACNA1C-Q1916R protein showed a reduction in amplitude of the current produced by the L-type calcium channel current. Moreover, in a human ventricular cell model used to stimulate action potential of endocardium and epicardium, the variant showed a 30% reduction in the conductance of the total ICa-L and AP duration at the level of 90% repolarization was reduced by 14.29% compared to WT (Liu_2017). A ClinVar submissions from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely benign, however, this was submitted prior to the Liu_2017 publication. Based on the evidence outlined above, the variant was classified as VUS - possibly benign. -

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 02, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 11, 2017

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

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.26

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

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

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.96

M_CAP

Benign

0.038

MetaRNN

Benign

0.014

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

MetaSVM

Benign

-0.91

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;N;N

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-1.7

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

REVEL

Benign

0.15

Sift

Benign

0.15

T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;D;T;D;.

Sift4G

Benign

0.69

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

Polyphen

0.49, 0.55, 0.23, 0.082, 0.35, 0.60, 0.28, 0.30, 0.45, 0.73, 0.63

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

Vest4

0.73

MVP

0.71

MPC

0.32

ClinPred

0.070

GERP RS

4.8

gMVP

0.60

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over