rs7413162

Positions:

chr1-115701256-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001232.4(CASQ2):c.1185C>T(p.Asp395=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.37 in 1,592,320 control chromosomes in the GnomAD database, including 108,018 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.40 ( 12002 hom., cov: 31)

Exomes 𝑓: 0.37 ( 96016 hom. )

Consequence

CASQ2
NM_001232.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -1.80

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 1-115701256-G-A is Benign according to our data. Variant chr1-115701256-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115701256-G-A is described in Lovd as [Pathogenic]. Variant chr1-115701256-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.8 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.447 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.1185C>T	p.Asp395=	synonymous_variant	11/11	ENST00000261448.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASQ2	ENST00000261448.6 linkuse as main transcript	c.1185C>T	p.Asp395=	synonymous_variant	11/11	1	NM_001232.4	P1	O14958-1
CASQ2	ENST00000488931.2 linkuse as main transcript	c.*557C>T		3_prime_UTR_variant, NMD_transcript_variant	13/13	3

Frequencies

GnomAD3 genomes

AF:

0.397

AC:

59905

AN:

150950

Hom.:

11979

Cov.:

show subpopulations

Gnomad AFR

AF:

0.452

Gnomad AMI

AF:

0.435

Gnomad AMR

AF:

0.431

Gnomad ASJ

AF:

0.391

Gnomad EAS

AF:

0.298

Gnomad SAS

AF:

0.417

Gnomad FIN

AF:

0.403

Gnomad MID

AF:

0.411

Gnomad NFE

AF:

0.359

Gnomad OTH

AF:

0.420

GnomAD3 exomes

AF:

0.381

AC:

95474

AN:

250554

Hom.:

18321

AF XY:

0.380

AC XY:

51479

AN XY:

135384

show subpopulations

Gnomad AFR exome

AF:

0.451

Gnomad AMR exome

AF:

0.440

Gnomad ASJ exome

AF:

0.406

Gnomad EAS exome

AF:

0.290

Gnomad SAS exome

AF:

0.408

Gnomad FIN exome

AF:

0.394

Gnomad NFE exome

AF:

0.355

Gnomad OTH exome

AF:

0.403

GnomAD4 exome

AF:

0.367

AC:

529264

AN:

1441250

Hom.:

96016

Cov.:

AF XY:

0.368

AC XY:

264296

AN XY:

717728

show subpopulations

Gnomad4 AFR exome

AF:

0.455

Gnomad4 AMR exome

AF:

0.441

Gnomad4 ASJ exome

AF:

0.400

Gnomad4 EAS exome

AF:

0.364

Gnomad4 SAS exome

AF:

0.405

Gnomad4 FIN exome

AF:

0.397

Gnomad4 NFE exome

AF:

0.356

Gnomad4 OTH exome

AF:

0.377

GnomAD4 genome

AF:

0.397

AC:

59982

AN:

151070

Hom.:

12002

Cov.:

AF XY:

0.401

AC XY:

29642

AN XY:

73838

show subpopulations

Gnomad4 AFR

AF:

0.452

Gnomad4 AMR

AF:

0.432

Gnomad4 ASJ

AF:

0.391

Gnomad4 EAS

AF:

0.298

Gnomad4 SAS

AF:

0.419

Gnomad4 FIN

AF:

0.403

Gnomad4 NFE

AF:

0.359

Gnomad4 OTH

AF:

0.418

Alfa

AF:

0.378

Hom.:

13164

Bravo

AF:

0.398

Asia WGS

AF:

0.400

AC:

1391

AN:

3478

EpiCase

AF:

0.366

EpiControl

AF:

0.376

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2014	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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 10, 2012	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 28, 2020	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Catecholaminergic polymorphic ventricular tachycardia 2

Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Catecholaminergic polymorphic ventricular tachycardia

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

Caudal regression sequence

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Neural tube defect

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 19, 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

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.13

DANN

Benign

0.57

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