1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAA

Position:

• chr1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAA

Variant summary

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

The NM_001232.4(CASQ2):​c.738-5del 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 0.028 (51 hom., cov: 0)
  • Exomes 𝑓: 0.13 (14 hom.)
• Consequence: CASQ2 NM_001232.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.516

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-GA-G is Benign according to our data. Variant chr1-115725557-GA-G is described in ClinVar as [Benign]. Clinvar id is 522226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GA-G is described in Lovd as [Benign]. Variant chr1-115725557-GA-G is described in Lovd as [Benign]. Variant chr1-115725557-GA-G is described in Lovd as [Likely_benign].
• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.14 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASQ2	NM_001232.4	c.738-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000261448.6	NP_001223.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6	c.738-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001232.4	ENSP00000261448	P1
CASQ2	ENST00000488931.2	c.*110-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		3		ENSP00000518226

Frequencies

GnomAD3 genomes AF: 0.0284 AC: 3233 AN: 113974 Hom.: 51 Cov.: 0

Gnomad AFR AF: 0.0456

Gnomad AMI AF: 0.00260

Gnomad AMR AF: 0.0215

Gnomad ASJ AF: 0.00669

Gnomad EAS AF: 0.00523

Gnomad SAS AF: 0.00973

Gnomad FIN AF: 0.00624

Gnomad MID AF: 0.0122

Gnomad NFE AF: 0.0260

Gnomad OTH AF: 0.0227

GnomAD4 exome AF: 0.132 AC: 164324 AN: 1244766 Hom.: 14 Cov.: 0 AF XY: 0.128 AC XY: 79523 AN XY: 619174

Gnomad4 AFR exome AF: 0.0884

Gnomad4 AMR exome AF: 0.0762

Gnomad4 ASJ exome AF: 0.113

Gnomad4 EAS exome AF: 0.0952

Gnomad4 SAS exome AF: 0.0885

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.132

GnomAD4 genome AF: 0.0284 AC: 3235 AN: 113944 Hom.: 51 Cov.: 0 AF XY: 0.0281 AC XY: 1486 AN XY: 52850

Gnomad4 AFR AF: 0.0456

Gnomad4 AMR AF: 0.0215

Gnomad4 ASJ AF: 0.00669

Gnomad4 EAS AF: 0.00525

Gnomad4 SAS AF: 0.00951

Gnomad4 FIN AF: 0.00624

Gnomad4 NFE AF: 0.0260

Gnomad4 OTH AF: 0.0226

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Dec 08, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Sep 06, 2019

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

CASQ2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs56889721; hg19: chr1-116268178;