rs4074536

Positions:

chr1-115768346-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001232.4(CASQ2):c.196A>G(p.Thr66Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 1,612,466 control chromosomes in the GnomAD database, including 79,340 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Synonymous variant affecting the same amino acid position (i.e. T66T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.35 ( 9637 hom., cov: 31)

Exomes 𝑓: 0.30 ( 69703 hom. )

Consequence

CASQ2
NM_001232.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 1.63

Variant links:

Genes affected

CASQ2 (HGNC:1513): (calsequestrin 2) The protein encoded by this gene specifies the cardiac muscle family member of the calsequestrin family. Calsequestrin is localized to the sarcoplasmic reticulum in cardiac and slow skeletal muscle cells. The protein is a calcium binding protein that stores calcium for muscle function. Mutations in this gene cause stress-induced polymorphic ventricular tachycardia, also referred to as catecholaminergic polymorphic ventricular tachycardia 2 (CPVT2), a disease characterized by bidirectional ventricular tachycardia that may lead to cardiac arrest. [provided by RefSeq, Jul 2008]

CASQ2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.7494435E-5).

BP6

Variant 1-115768346-T-C is Benign according to our data. Variant chr1-115768346-T-C is described in ClinVar as [Benign]. Clinvar id is 44160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115768346-T-C is described in Lovd as [Pathogenic]. Variant chr1-115768346-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASQ2	NM_001232.4 linkuse as main transcript	c.196A>G	p.Thr66Ala	missense_variant	1/11	ENST00000261448.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASQ2	ENST00000261448.6 linkuse as main transcript	c.196A>G	p.Thr66Ala	missense_variant	1/11	1	NM_001232.4	P1	O14958-1
CASQ2	ENST00000488931.2 linkuse as main transcript	c.-81A>G		5_prime_UTR_variant, NMD_transcript_variant	2/13	3

Frequencies

GnomAD3 genomes

AF:

0.345

AC:

52384

AN:

151828

Hom.:

9617

Cov.:

show subpopulations

Gnomad AFR

AF:

0.448

Gnomad AMI

AF:

0.462

Gnomad AMR

AF:

0.347

Gnomad ASJ

AF:

0.252

Gnomad EAS

AF:

0.530

Gnomad SAS

AF:

0.312

Gnomad FIN

AF:

0.286

Gnomad MID

AF:

0.380

Gnomad NFE

AF:

0.283

Gnomad OTH

AF:

0.343

GnomAD3 exomes

AF:

0.329

AC:

82656

AN:

251288

Hom.:

14499

AF XY:

0.324

AC XY:

43994

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.454

Gnomad AMR exome

AF:

0.360

Gnomad ASJ exome

AF:

0.261

Gnomad EAS exome

AF:

0.549

Gnomad SAS exome

AF:

0.302

Gnomad FIN exome

AF:

0.277

Gnomad NFE exome

AF:

0.289

Gnomad OTH exome

AF:

0.326

GnomAD4 exome

AF:

0.304

AC:

443580

AN:

1460520

Hom.:

69703

Cov.:

AF XY:

0.303

AC XY:

219822

AN XY:

726622

show subpopulations

Gnomad4 AFR exome

AF:

0.454

Gnomad4 AMR exome

AF:

0.359

Gnomad4 ASJ exome

AF:

0.259

Gnomad4 EAS exome

AF:

0.520

Gnomad4 SAS exome

AF:

0.304

Gnomad4 FIN exome

AF:

0.275

Gnomad4 NFE exome

AF:

0.290

Gnomad4 OTH exome

AF:

0.316

GnomAD4 genome

AF:

0.345

AC:

52445

AN:

151946

Hom.:

9637

Cov.:

AF XY:

0.347

AC XY:

25742

AN XY:

74276

show subpopulations

Gnomad4 AFR

AF:

0.448

Gnomad4 AMR

AF:

0.347

Gnomad4 ASJ

AF:

0.252

Gnomad4 EAS

AF:

0.528

Gnomad4 SAS

AF:

0.312

Gnomad4 FIN

AF:

0.286

Gnomad4 NFE

AF:

0.283

Gnomad4 OTH

AF:

0.346

Alfa

AF:

0.309

Hom.:

19547

Bravo

AF:

0.361

TwinsUK

AF:

0.290

AC:

1077

ALSPAC

AF:

0.298

AC:

1149

ESP6500AA

AF:

0.438

AC:

1928

ESP6500EA

AF:

0.289

AC:

2486

ExAC

AF:

0.326

AC:

39634

Asia WGS

AF:

0.382

AC:

1330

AN:

3478

EpiCase

AF:

0.297

EpiControl

AF:

0.303

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 2

Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 30, 2011	benign based on high population frequency (rs4074536) -

Catecholaminergic polymorphic ventricular tachycardia

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

This variant is associated with the following publications: (PMID: 24025405, 21076409, 30012220) -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 23, 2015

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

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.77

CADD

Benign

1.7

DANN

Benign

0.18

DEOGEN2

Benign

0.086

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.077

LIST_S2

Benign

0.0078

MetaRNN

Benign

0.000077

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.7

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.30

PROVEAN

Benign

0.49

REVEL

Benign

0.086

Sift

Benign

0.94

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.010

MPC

0.046

ClinPred

0.00022

GERP RS

3.4

Varity_R

0.083

gMVP

0.20

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