rs727503835

Positions:

chr12-2664914-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2BP4_StrongBS2

The NM_000719.7(CACNA1C):c.4322C>T(p.Thr1441Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,832 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 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.13

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 Benign. Variant got -7 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=0.021968812).

BS2

High AC in GnomAd4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.4322C>T	p.Thr1441Met	missense_variant	35/47	ENST00000399655.6	NP_000710.5
CACNA1C	NM_001167623.2 linkuse as main transcript	c.4322C>T	p.Thr1441Met	missense_variant	35/47	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.4322C>T	p.Thr1441Met	missense_variant	35/47	5	NM_001167623.2	ENSP00000382512		Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.4322C>T	p.Thr1441Met	missense_variant	35/47	1	NM_000719.7	ENSP00000382563		Q13936-12

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.0175

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

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249582

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135294

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000354

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461632

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000118

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74364

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000772

Hom.:

Bravo

AF:

0.000174

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 13, 2014	- -
Uncertain significance, no assertion criteria provided	clinical testing	Genetics and Genomic Medicine Centre, NeuroGen Healthcare, NeuroGen Healthcare	Apr 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 16, 2023	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Identified in a patient with suspected Brugada syndrome in published literature; however, detailed clinical information was not provided (Marschall et al., 2019); This variant is associated with the following publications: (PMID: 31737537) -

Long QT syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 1441 of the CACNA1C protein (p.Thr1441Met). This variant is present in population databases (rs727503835, gnomAD 0.004%). This missense change has been observed in individual(s) with Brugada syndrome (PMID: 31737537). ClinVar contains an entry for this variant (Variation ID: 166773). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CACNA1C protein function. 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

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 05, 2023

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

Uncertain

0.023

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

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

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.82

M_CAP

Uncertain

0.28

MetaRNN

Benign

0.022

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

0.92

MutationAssessor

Benign

1.7

.;.;.;.;.;.;.;.;.;.;L;.;.;.;.;.;.;.;.;.;.;.;.

MutationTaster

Benign

0.67

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

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.0

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

REVEL

Uncertain

0.46

Sift

Benign

0.099

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

Sift4G

Benign

0.098

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

Polyphen

0.96, 0.91, 0.89, 0.96, 0.95, 0.98, 0.88, 0.98, 1.0, 0.97

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

Vest4

0.30

MVP

0.75

MPC

1.2

ClinPred

0.64

GERP RS

4.1

gMVP

0.63

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