rs121912776

Positions:

chr12-2115290-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3PP5

The NM_000719.7(CACNA1C):c.116C>T(p.Ala39Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A39A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1O:2

Conservation

PhyloP100: 5.67

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.836

PP5

Variant 12-2115290-C-T is Pathogenic according to our data. Variant chr12-2115290-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 17635.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.116C>T	p.Ala39Val	missense_variant	2/47	ENST00000399655.6
CACNA1C	NM_001167623.2 linkuse as main transcript	c.116C>T	p.Ala39Val	missense_variant	2/47	ENST00000399603.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.116C>T	p.Ala39Val	missense_variant	2/47	5	NM_001167623.2		Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.116C>T	p.Ala39Val	missense_variant	2/47	1	NM_000719.7		Q13936-12

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.94e-7

AC:

AN:

1440238

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

714900

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000120

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1Other:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Brugada syndrome 3

Pathogenic:1Other:1

not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 30, 2007	- -

Brugada syndrome

Other:1

not provided, no classification provided

literature only

Cardiovascular Biomedical Research Unit, Royal Brompton & Harefield NHS Foundation Trust

This variant has been reported as associated with Brugada syndrome in the following publications (PMID:17224476;PMID:20817017;PMID:22385640). This is a literature report, and does not necessarily reflect the clinical interpretation of the Imperial College / Royal Brompton Cardiovascular Genetics laboratory. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.022

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

Eigen

Pathogenic

0.68

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

1.0

M_CAP

Uncertain

0.20

MetaRNN

Pathogenic

0.84

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Benign

0.34

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

MutationTaster

Benign

1.0

A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A;A

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.4

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

REVEL

Pathogenic

0.72

Sift

Pathogenic

0.0

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

Sift4G

Pathogenic

0.0

D;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, 0.14, 1.0, 0.98

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

Vest4

0.64, 0.65, 0.50, 0.65, 0.65, 0.56, 0.66, 0.61, 0.70, 0.58, 0.64, 0.61, 0.58, 0.65, 0.50, 0.61, 0.66, 0.63, 0.62, 0.64, 0.83

MutPred

0.55

.;Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);Gain of catalytic residue at E41 (P = 0.0095);

MVP

0.97

MPC

2.1

ClinPred

0.98

GERP RS

5.8

gMVP

0.67

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

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