1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAAAA

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP6_Very_StrongBS1

The NM_001232.4(CASQ2):c.738-8_738-5delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,370,536 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 0)

Exomes 𝑓: 0.014 ( 0 hom. )

Consequence

CASQ2
NM_001232.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.72

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 -10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 1-115725557-GAAAA-G is Benign according to our data. Variant chr1-115725557-GAAAA-G is described in ClinVar as [Likely_benign]. Clinvar id is 522228.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAAAA-G is described in Lovd as [Benign]. Variant chr1-115725557-GAAAA-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0145 (18204/1256546) while in subpopulation AFR AF= 0.033 (910/27588). AF 95% confidence interval is 0.0312. There are 0 homozygotes in gnomad4_exome. There are 8959 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ2	NM_001232.4 link	c.738-8_738-5delTTTT		splice_region_variant, intron_variant	Intron 6 of 10	ENST00000261448.6	NP_001223.2	O14958-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6 link	c.738-8_738-5delTTTT		splice_region_variant, intron_variant	Intron 6 of 10	1	NM_001232.4	ENSP00000261448.5		O14958-1
CASQ2	ENST00000488931.2 link	n.110-8_110-5delTTTT		splice_region_variant, intron_variant	Intron 8 of 12	3		ENSP00000518226.1

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

114020

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000357

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000334

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000567

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000176

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0145

AC:

18204

AN:

1256546

Hom.:

AF XY:

0.0143

AC XY:

8959

AN XY:

625266

show subpopulations

Gnomad4 AFR exome

AF:

0.0330

Gnomad4 AMR exome

AF:

0.0176

Gnomad4 ASJ exome

AF:

0.0142

Gnomad4 EAS exome

AF:

0.0239

Gnomad4 SAS exome

AF:

0.0111

Gnomad4 FIN exome

AF:

0.0192

Gnomad4 NFE exome

AF:

0.0134

Gnomad4 OTH exome

AF:

0.0172

GnomAD4 genome

AF:

0.000132

AC:

AN:

113990

Hom.:

Cov.:

AF XY:

0.000170

AC XY:

AN XY:

52880

show subpopulations

Gnomad4 AFR

AF:

0.000357

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000334

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000567

Gnomad4 NFE

AF:

0.0000176

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Feb 11, 2020

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

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

- -

Sep 23, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CASQ2 c.738-8_738-5delTTTT alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 179292 control chromosomes (gnomAD). However, the variant is located in a homopolymer region of 20 Ts, which is a highly polymorphic region. Therefore, suggesting the region is tolerable to changes in length of poly Ts. To our knowledge, no occurrence of c.738-8_738-5delTTTT in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submission (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:3

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 2

Benign:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 11, 2016

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Benign:1

Nov 02, 2018

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Dec 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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