rs752000790

Positions:

chr12-2115376-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_000719.7(CACNA1C):c.202G>A(p.Ala68Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000141 in 1,606,346 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. 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. A68V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 34)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

CACNA1C
NM_000719.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:3

Conservation

PhyloP100: 4.69

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 Likely_benign. Variant got -6 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=0.13323656).

BP6

Variant 12-2115376-G-A is Benign according to our data. Variant chr12-2115376-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 190709.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=6, Likely_benign=2, Benign=1}.

BS2

High AC in GnomAd4 at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CACNA1C	NM_000719.7 linkuse as main transcript	c.202G>A	p.Ala68Thr	missense_variant	2/47	ENST00000399655.6
CACNA1C	NM_001167623.2 linkuse as main transcript	c.202G>A	p.Ala68Thr	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.202G>A	p.Ala68Thr	missense_variant	2/47	5	NM_001167623.2		Q13936-37
CACNA1C	ENST00000399655.6 linkuse as main transcript	c.202G>A	p.Ala68Thr	missense_variant	2/47	1	NM_000719.7		Q13936-12

Frequencies

GnomAD3 genomes

AF:

0.000131

AC:

AN:

152248

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:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000149

AC:

AN:

234160

Hom.:

AF XY:

0.000164

AC XY:

AN XY:

128192

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000301

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000339

Gnomad FIN exome

AF:

0.000105

Gnomad NFE exome

AF:

0.000292

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000142

AC:

206

AN:

1454098

Hom.:

Cov.:

AF XY:

0.000144

AC XY:

104

AN XY:

723082

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000228

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000352

Gnomad4 FIN exome

AF:

0.000119

Gnomad4 NFE exome

AF:

0.000174

Gnomad4 OTH exome

AF:

0.0000499

GnomAD4 genome

AF:

0.000131

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74372

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:

0.000188

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000292

Hom.:

Bravo

AF:

0.0000756

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Timothy syndrome

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Uncertain significance. The following ACMG criteria were applied in classifying this variant: PP3,PP4. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues	Jan 31, 2018	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 06, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in association with LQTS, arrhythmia, primary electric disease (PED), and HCM in published literature; at least one patient harbored additional cardiogenetic variants (PMID: 28341588, 23631430, 27231019, 31293105); This variant is associated with the following publications: (PMID: 23631430, 27231019, 31737537, 31293105, 35882527, 28341588) -

Brugada syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 06, 2017

Variant summary: The CACNA1C c.202G>A (p.Ala68Thr) variant involves the alteration of a conserved nucleotide and 2/3 in silico tools predict a benign outcome for this variant (SNPsandGO and MutationTaster not captured here due to low reliability index and p-value, respectively). This variant was found in 41/261782 control chromosomes at a frequency of 0.0001566, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.000309 (37/119594). This frequency is about 31 times the estimated maximal expected allele frequency of a pathogenic CACNA1C variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. This variant has been reported in multiple affected individuals without strong evidence for casualty. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, without evidence for independent evaluation. Taken together, this variant is classified as likely benign. -

Long QT syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2021

This alteration is classified as 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

-0.23

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Benign

0.30

DEOGEN2

Benign

0.0046

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

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.096

FATHMM_MKL

Uncertain

0.97

M_CAP

Benign

0.019

MetaRNN

Benign

0.13

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

0.82

MutationAssessor

Benign

-0.69

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

MutationTaster

Benign

0.82

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

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.8

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

Benign

0.28

Sift

Benign

0.090

T;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

0.054, 0.15, 0.068, 0.24, 0.20, 0.067

.;.;B;.;B;B;B;B;B;B;B;B;B;B;B;B;B;.;B;B;.;.;.;.

Vest4

0.22, 0.21, 0.26, 0.22, 0.24, 0.18, 0.22, 0.24, 0.25, 0.21, 0.19, 0.21, 0.24, 0.25, 0.22, 0.17, 0.22, 0.20, 0.23, 0.27, 0.21, 0.19

MVP

0.90

MPC

1.0

ClinPred

0.080

GERP RS

5.6

gMVP

0.76

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