rs10801999

Positions:

chr1-115768316-C-T

Variant summary

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

The ENST00000261448.6(CASQ2):c.226G>A(p.Val76Met) variant causes a missense change. The variant allele was found at a frequency of 0.00964 in 1,610,530 control chromosomes in the GnomAD database, including 824 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V76A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.014 ( 88 hom., cov: 32)

Exomes 𝑓: 0.0091 ( 736 hom. )

Consequence

CASQ2
ENST00000261448.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 5.86

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=0.002249509).

BP6

Variant 1-115768316-C-T is Benign according to our data. Variant chr1-115768316-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 44162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115768316-C-T is described in Lovd as [Benign]. Variant chr1-115768316-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0757 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASQ2	NM_001232.4 linkuse as main transcript	c.226G>A	p.Val76Met	missense_variant	1/11	ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6 linkuse as main transcript	c.226G>A	p.Val76Met	missense_variant	1/11	1	NM_001232.4	ENSP00000261448	P1	O14958-1
CASQ2	ENST00000488931.2 linkuse as main transcript	c.-51G>A		5_prime_UTR_variant, NMD_transcript_variant	2/13	3		ENSP00000518226

Frequencies

GnomAD3 genomes

AF:

0.0144

AC:

2192

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00299

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0792

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0713

Gnomad SAS

AF:

0.0182

Gnomad FIN

AF:

0.0272

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00115

Gnomad OTH

AF:

0.0168

GnomAD3 exomes

AF:

0.0317

AC:

7968

AN:

251022

Hom.:

544

AF XY:

0.0262

AC XY:

3551

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.00221

Gnomad AMR exome

AF:

0.158

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.0658

Gnomad SAS exome

AF:

0.0125

Gnomad FIN exome

AF:

0.0261

Gnomad NFE exome

AF:

0.00138

Gnomad OTH exome

AF:

0.0237

GnomAD4 exome

AF:

0.00914

AC:

13332

AN:

1458268

Hom.:

736

Cov.:

AF XY:

0.00870

AC XY:

6313

AN XY:

725764

show subpopulations

Gnomad4 AFR exome

AF:

0.00168

Gnomad4 AMR exome

AF:

0.149

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.0752

Gnomad4 SAS exome

AF:

0.0131

Gnomad4 FIN exome

AF:

0.0254

Gnomad4 NFE exome

AF:

0.000532

Gnomad4 OTH exome

AF:

0.00924

GnomAD4 genome

AF:

0.0144

AC:

2196

AN:

152262

Hom.:

Cov.:

AF XY:

0.0174

AC XY:

1292

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00298

Gnomad4 AMR

AF:

0.0794

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0714

Gnomad4 SAS

AF:

0.0182

Gnomad4 FIN

AF:

0.0272

Gnomad4 NFE

AF:

0.00115

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.00758

Hom.:

113

Bravo

AF:

0.0199

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.0251

AC:

3042

Asia WGS

AF:

0.0310

AC:

108

AN:

3478

EpiCase

AF:

0.000654

EpiControl

AF:

0.000948

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 06, 2011	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Catecholaminergic polymorphic ventricular tachycardia 2

Benign:4

Likely 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 04, 2016	- -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Nov 18, 2015

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 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

0.23

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.0022

MetaSVM

Uncertain

-0.053

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.69

REVEL

Benign

0.25

Sift

Benign

0.45

Sift4G

Benign

0.32

Polyphen

0.82

Vest4

0.23

MPC

0.32

ClinPred

0.021

GERP RS

5.5

Varity_R

0.29

gMVP

0.64

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