1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAAAA

Variant summary

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

The NM_001232.4(CASQ2):c.738-5_738-4insT 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 0.052 (319 hom., cov: 0)
  • Exomes 𝑓: 0.035 (79 hom.)
• Consequence: CASQ2 NM_001232.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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-G-GA is Benign according to our data. Variant chr1-115725557-G-GA is described in ClinVar as [Benign]. Clinvar id is 915585.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.0521 AC: 5925 AN: 113780 Hom.: 319 Cov.: 0

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0901

Gnomad ASJ AF: 0.000669

Gnomad EAS AF: 0.0643

Gnomad SAS AF: 0.00700

Gnomad FIN AF: 0.0179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00259

Gnomad OTH AF: 0.0395

GnomAD4 exome AF: 0.0349 AC: 44129 AN: 1264726 Hom.: 79 Cov.: 0 AF XY: 0.0348 AC XY: 21900 AN XY: 629560

Gnomad4 AFR exome AF: 0.0787

Gnomad4 AMR exome AF: 0.0736

Gnomad4 ASJ exome AF: 0.0475

Gnomad4 EAS exome AF: 0.0409

Gnomad4 SAS exome AF: 0.0463

Gnomad4 FIN exome AF: 0.0379

Gnomad4 NFE exome AF: 0.0311

Gnomad4 OTH exome AF: 0.0354

GnomAD4 genome AF: 0.0521 AC: 5930 AN: 113752 Hom.: 319 Cov.: 0 AF XY: 0.0541 AC XY: 2854 AN XY: 52764

Gnomad4 AFR AF: 0.145

Gnomad4 AMR AF: 0.0901

Gnomad4 ASJ AF: 0.000669

Gnomad4 EAS AF: 0.0642

Gnomad4 SAS AF: 0.00675

Gnomad4 FIN AF: 0.0179

Gnomad4 NFE AF: 0.00259

Gnomad4 OTH AF: 0.0395

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Nov 26, 2019

- -

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;C2677794:Catecholaminergic polymorphic ventricular tachycardia 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 17, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2019

- -

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;