rs77775029

Variant summary

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

The NM_001232.4(CASQ2):c.1014+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00398 in 1,609,258 control chromosomes in the GnomAD database, including 187 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.020 ( 90 hom., cov: 33)

Exomes 𝑓: 0.0023 ( 97 hom. )

Consequence

CASQ2
NM_001232.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 1.04

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 (BayesDel_noAF=-0.72).

BP6

Variant 1-115702912-G-A is Benign according to our data. Variant chr1-115702912-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 44153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115702912-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0641 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.1014+9C>T		intron_variant		ENST00000261448.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASQ2	ENST00000261448.6 linkuse as main transcript	c.1014+9C>T		intron_variant		1	NM_001232.4	P1	O14958-1
CASQ2	ENST00000488931.2 linkuse as main transcript	c.*386+9C>T		intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0195

AC:

2973

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0660

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00857

Gnomad ASJ

AF:

0.00490

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.000735

Gnomad OTH

AF:

0.0162

GnomAD3 exomes

AF:

0.00528

AC:

1314

AN:

248908

Hom.:

AF XY:

0.00406

AC XY:

546

AN XY:

134494

show subpopulations

Gnomad AFR exome

AF:

0.0665

Gnomad AMR exome

AF:

0.00344

Gnomad ASJ exome

AF:

0.00492

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000265

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000665

Gnomad OTH exome

AF:

0.00362

GnomAD4 exome

AF:

0.00234

AC:

3413

AN:

1456952

Hom.:

Cov.:

AF XY:

0.00209

AC XY:

1512

AN XY:

724894

show subpopulations

Gnomad4 AFR exome

AF:

0.0683

Gnomad4 AMR exome

AF:

0.00449

Gnomad4 ASJ exome

AF:

0.00546

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000256

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000348

Gnomad4 OTH exome

AF:

0.00543

GnomAD4 genome

AF:

0.0196

AC:

2985

AN:

152306

Hom.:

Cov.:

AF XY:

0.0186

AC XY:

1385

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0661

Gnomad4 AMR

AF:

0.00850

Gnomad4 ASJ

AF:

0.00490

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000735

Gnomad4 OTH

AF:

0.0161

Alfa

AF:

0.0106

Hom.:

Bravo

AF:

0.0223

Asia WGS

AF:

0.00693

AC:

AN:

3476

EpiCase

AF:

0.00109

EpiControl

AF:

0.00131

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jan 14, 2016	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 22, 2012	5.9% (221/3738) Afr Amer chrom (ESP) -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Catecholaminergic polymorphic ventricular tachycardia

Benign:2

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

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 25, 2016

- -

Caudal regression sequence

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

Cadd

Benign

1.2

Dann

Benign

0.68

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