12-2115265-A-G

Position:

chr12-2115265-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_000719.7(CACNA1C):c.91A>G(p.Asn31Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000314 in 1,592,054 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.56

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.2896582).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.91A>G	p.Asn31Asp	missense_variant	2/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 linkuse as main transcript	c.91A>G	p.Asn31Asp	missense_variant	2/47	ENST00000399603.6	NP_001161095.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CACNA1C	ENST00000399603.6 linkuse as main transcript	c.91A>G	p.Asn31Asp	missense_variant	2/47	5	NM_001167623.2	ENSP00000382512		Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.91A>G	p.Asn31Asp	missense_variant	2/47	1	NM_000719.7	ENSP00000382563		Q13936-12

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152258

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000916

AC:

AN:

218382

Hom.:

AF XY:

0.00000843

AC XY:

AN XY:

118678

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 SAS exome

AF:

0.0000732

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000278

AC:

AN:

1439678

Hom.:

Cov.:

AF XY:

0.00000280

AC XY:

AN XY:

713390

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:

0.0000479

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000656

AC:

AN:

152376

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74526

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000166

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 24, 2013

p.Asn31Asp (AAT>GAT): c.91 A>G in exon 2 of the CACNA1C gene (NM_000719.6). The Asn31Asp variant in the CACNA1C gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Asn31Asp was not observed in approximately 6000 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The Asn31Asp variant results in a semi-conservative amino acid substitution of a neutral Asparagine with a negatively-charged Aspartic acid at a position that is conserved across species. However, in silico analysis predicts Asn31Asp is benign to the protein structure/function. Mutations in nearby residues have not been reported, indicating this region of the protein may tolerate change. With the clinical and molecular information available at this time, we cannot definitively determine if Asn31Asp is a disease-causing mutation or a rare benign variant. The variant is found in LQT panel(s). -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 22, 2020

In summary, this is a rare missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. This variant is present in population databases (rs531598856, ExAC 0.03%) but has not been reported in the literature in individuals with a CACNA1C-related disease. ClinVar contains an entry for this variant (Variation ID: 190678). This sequence change replaces asparagine with aspartic acid at codon 31 of the CACNA1C protein (p.Asn31Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0090

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

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.99

M_CAP

Uncertain

0.085

MetaRNN

Benign

0.29

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

MetaSVM

Pathogenic

0.88

MutationAssessor

Benign

0.0

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

MutationTaster

Benign

1.0

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

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-3.6

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

Uncertain

0.37

Sift

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

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

0.53, 0.075, 0.85, 0.74, 0.42, 0.29

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

Vest4

0.41, 0.38, 0.39, 0.37, 0.39, 0.40, 0.38, 0.37, 0.38, 0.42, 0.40, 0.37, 0.38, 0.41, 0.40, 0.38, 0.48

MutPred

0.33

.;Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);Gain of catalytic residue at M30 (P = 0.0011);

MVP

0.91

MPC

2.1

ClinPred

0.53

GERP RS

5.8

gMVP

0.55

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