1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAAAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001232.4(CASQ2):c.738-6_738-5del variant causes a splice region, splice polypyrimidine tract, 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, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 1.18

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 -16 ACMG points.

• BP6: Variant 1-115725557-GAA-G is Benign according to our data. Variant chr1-115725557-GAA-G is described in ClinVar 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 Lovd as [Benign]. Variant chr1-115725557-GAA-G is described in Lovd as [Likely_benign].
• 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/exons	MANE	UniProt
CASQ2	NM_001232.4	c.738-6_738-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000261448.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASQ2	ENST00000261448.6	c.738-6_738-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001232.4	P1
CASQ2	ENST00000488931.2	c.*110-6_*110-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		3

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

Gnomad4 AFR exome AF: 0.242

Gnomad4 AMR exome AF: 0.218

Gnomad4 ASJ exome AF: 0.293

Gnomad4 EAS exome AF: 0.317

Gnomad4 SAS exome AF: 0.288

Gnomad4 FIN exome AF: 0.263

Gnomad4 NFE exome AF: 0.333

Gnomad4 OTH exome AF: 0.320

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

Gnomad4 AFR AF: 0.372

Gnomad4 AMR AF: 0.504

Gnomad4 ASJ AF: 0.541

Gnomad4 EAS AF: 0.580

Gnomad4 SAS AF: 0.579

Gnomad4 FIN AF: 0.524

Gnomad4 NFE AF: 0.538

Gnomad4 OTH AF: 0.512

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	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 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 29, 2019	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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 12, 2018	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Aug 12, 2020

- -

Catecholaminergic polymorphic ventricular tachycardia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Apr 11, 2023

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 20, 2024

- -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs56889721; hg19: chr1-116268178;