rs7413162

Variant names:

• chr1-115701256-G-A
• rs7413162
• NM_001232.4:c.1185C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001232.4(CASQ2):​c.1185C>T​(p.Asp395Asp) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:17
• Conservation: PhyloP100: -1.80

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]

ACMG classification

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 rank	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.1185C>T	p.Asp395Asp	synonymous_variant	Exon 11 of 11	ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.1185C>T	p.Asp395Asp	synonymous_variant	Exon 11 of 11	1	NM_001232.4	ENSP00000261448.5
CASQ2	ENST00000488931.2	n.*557C>T		non_coding_transcript_exon_variant	Exon 13 of 13	3		ENSP00000518226.1
CASQ2	ENST00000488931.2	n.*557C>T		3_prime_UTR_variant	Exon 13 of 13	3		ENSP00000518226.1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 59905 AN: 150950 Hom.: 11979 Cov.: 31

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

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.: 30 AF XY: 0.368 AC XY: 264296 AN XY: 717728

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.: 31 AF XY: 0.401 AC XY: 29642 AN XY: 73838

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:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Apr 10, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 09, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 10, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 28, 2020

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 2 Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 11, 2023

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 21, 2015

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 23, 2022

Cohesion Phenomics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Caudal regression sequence Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neural tube defect Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Jun 19, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Other links and lift over

dbSNP: rs7413162; hg19: chr1-116243877; COSMIC: COSV54770824; COSMIC: COSV54770824;