chr1-115725557-GAA-G

Variant names:

• chr1-115725557-GAA-G
• rs56889721
• NM_001232.4:c.738-6_738-5delTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001232.4(CASQ2):​c.738-6_738-5delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (12994 hom., cov: 0)
  • Exomes 𝑓: 0.32 (1242 hom.)
  • Failed GnomAD Quality Control
• Consequence: CASQ2 NM_001232.4 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.18
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• catecholaminergic polymorphic ventricular tachycardia

  Inheritance: AD, AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• catecholaminergic polymorphic ventricular tachycardia 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant 1-115725557-GAA-G is Benign according to our data. Variant chr1-115725557-GAA-G is described in CliVar as Benign. Clinvar id is 402495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAA-G is described in CliVar as Benign. Clinvar id is 402495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAA-G is described in CliVar as Benign. Clinvar id is 402495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAA-G is described in CliVar as Benign. Clinvar id is 402495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAA-G is described in CliVar as Benign. Clinvar id is 402495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAA-G is described in CliVar as Benign. Clinvar id is 402495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAA-G is described in CliVar as Benign. Clinvar id is 402495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.56 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.738-6_738-5delTT		splice_region_variant, intron_variant	Intron 6 of 10	1	NM_001232.4	ENSP00000261448.5

Frequencies

GnomAD3 genomes AF: 0.493 AC: 55955 AN: 113542 Hom.: 13012 Cov.: 0

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.641

Gnomad AMR AF: 0.504

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.581

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.524

Gnomad MID AF: 0.618

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.512

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.322 AC: 394566 AN: 1224260 Hom.: 1242 AF XY: 0.320 AC XY: 194243 AN XY: 607528

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.242 AC: 6522 AN: 26934

American (AMR) AF: 0.218 AC: 6292 AN: 28834

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 6173 AN: 21094

East Asian (EAS) AF: 0.317 AC: 10837 AN: 34230

South Asian (SAS) AF: 0.288 AC: 18946 AN: 65762

European-Finnish (FIN) AF: 0.263 AC: 9148 AN: 34742

Middle Eastern (MID) AF: 0.343 AC: 1196 AN: 3488

European-Non Finnish (NFE) AF: 0.333 AC: 319215 AN: 958426

Other (OTH) AF: 0.320 AC: 16237 AN: 50750

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.493 AC: 55922 AN: 113514 Hom.: 12994 Cov.: 0 AF XY: 0.491 AC XY: 25882 AN XY: 52664

African (AFR) AF: 0.372 AC: 11434 AN: 30744

American (AMR) AF: 0.504 AC: 5175 AN: 10276

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1609 AN: 2972

East Asian (EAS) AF: 0.580 AC: 2196 AN: 3784

South Asian (SAS) AF: 0.579 AC: 1875 AN: 3236

European-Finnish (FIN) AF: 0.524 AC: 1843 AN: 3518

Middle Eastern (MID) AF: 0.625 AC: 140 AN: 224

European-Non Finnish (NFE) AF: 0.538 AC: 30378 AN: 56466

Other (OTH) AF: 0.512 AC: 785 AN: 1534

Alfa AF: 0.173 Hom.: 284

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 29, 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.738-6_738-5delTT 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 allele was found at a frequency of 0.46 in 17666 control chromosomes in the gnomAD database, including 169 homozygotes. The observed variant frequency is approximately 102-folds over the estimated maximal expected allele frequency for a pathogenic variant in CASQ2 causing Arrhythmia phenotype (0.0045), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.738-6_738-5delTT in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions (evaluation after 2014) cites the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:2

Jun 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

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

- -

Cardiomyopathy Benign:1

Aug 12, 2020

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 2 Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs56889721; hg19: chr1-116268178;