chr1-115740722-A-G

Position:

chr1-115740722-A-G

Variant summary

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

The NM_001232.4(CASQ2):c.420+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.834 in 1,571,264 control chromosomes in the GnomAD database, including 558,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.71 ( 42138 hom., cov: 30)

Exomes 𝑓: 0.85 ( 516157 hom. )

Consequence

CASQ2
NM_001232.4 splice_donor_region, intron

Scores

Splicing: ADA: 0.01831

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.489

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=-0.89).

BP6

Variant 1-115740722-A-G is Benign according to our data. Variant chr1-115740722-A-G is described in ClinVar as [Benign]. Clinvar id is 44163.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115740722-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.869 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.420+6T>C		splice_donor_region_variant, intron_variant		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.420+6T>C		splice_donor_region_variant, intron_variant		1	NM_001232.4	ENSP00000261448	P1	O14958-1
CASQ2	ENST00000488931.2 linkuse as main transcript	c.144+6T>C		splice_donor_region_variant, intron_variant, NMD_transcript_variant		3		ENSP00000518226

Frequencies

GnomAD3 genomes

AF:

0.711

AC:

108052

AN:

151940

Hom.:

42127

Cov.:

show subpopulations

Gnomad AFR

AF:

0.365

Gnomad AMI

AF:

0.967

Gnomad AMR

AF:

0.763

Gnomad ASJ

AF:

0.856

Gnomad EAS

AF:

0.762

Gnomad SAS

AF:

0.740

Gnomad FIN

AF:

0.817

Gnomad MID

AF:

0.791

Gnomad NFE

AF:

0.875

Gnomad OTH

AF:

0.747

GnomAD3 exomes

AF:

0.796

AC:

199565

AN:

250784

Hom.:

81593

AF XY:

0.806

AC XY:

109246

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.352

Gnomad AMR exome

AF:

0.774

Gnomad ASJ exome

AF:

0.846

Gnomad EAS exome

AF:

0.770

Gnomad SAS exome

AF:

0.746

Gnomad FIN exome

AF:

0.813

Gnomad NFE exome

AF:

0.875

Gnomad OTH exome

AF:

0.817

GnomAD4 exome

AF:

0.847

AC:

1202361

AN:

1419206

Hom.:

516157

Cov.:

AF XY:

0.846

AC XY:

599726

AN XY:

708736

show subpopulations

Gnomad4 AFR exome

AF:

0.344

Gnomad4 AMR exome

AF:

0.774

Gnomad4 ASJ exome

AF:

0.845

Gnomad4 EAS exome

AF:

0.678

Gnomad4 SAS exome

AF:

0.750

Gnomad4 FIN exome

AF:

0.814

Gnomad4 NFE exome

AF:

0.883

Gnomad4 OTH exome

AF:

0.820

GnomAD4 genome

AF:

0.711

AC:

108081

AN:

152058

Hom.:

42138

Cov.:

AF XY:

0.711

AC XY:

52849

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.365

Gnomad4 AMR

AF:

0.764

Gnomad4 ASJ

AF:

0.856

Gnomad4 EAS

AF:

0.762

Gnomad4 SAS

AF:

0.740

Gnomad4 FIN

AF:

0.817

Gnomad4 NFE

AF:

0.875

Gnomad4 OTH

AF:

0.750

Alfa

AF:

0.843

Hom.:

107312

Bravo

AF:

0.695

Asia WGS

AF:

0.703

AC:

2443

AN:

3476

EpiCase

AF:

0.872

EpiControl

AF:

0.874

ClinVar

Significance: Benign

Submissions summary: Benign:12

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	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 16, 2011	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Catecholaminergic polymorphic ventricular tachycardia

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

5.8

DANN

Benign

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.018

dbscSNV1_RF

Benign

0.076

SpliceAI score (max)

0.020

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