1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAAAAA

Variant summary

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

The NM_001232.4(CASQ2):c.738-7_738-5del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0979 in 1,340,408 control chromosomes in the GnomAD database, including 422 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.051 (412 hom., cov: 0)
  • Exomes 𝑓: 0.10 (10 hom.)
• Consequence: CASQ2 NM_001232.4 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.72

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-GAAA-G is Benign according to our data. Variant chr1-115725557-GAAA-G is described in ClinVar as [Benign]. Clinvar id is 522227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAAA-G is described in Lovd as [Benign]. Variant chr1-115725557-GAAA-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.167 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASQ2	NM_001232.4	c.738-7_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.738-7_738-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001232.4	P1
CASQ2	ENST00000488931.2	c.*110-7_*110-5del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, NMD_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0507 AC: 5782 AN: 113970 Hom.: 411 Cov.: 0

Gnomad AFR AF: 0.171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.00501

Gnomad EAS AF: 0.00366

Gnomad SAS AF: 0.00395

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.0163

Gnomad NFE AF: 0.00325

Gnomad OTH AF: 0.0396

GnomAD4 exome AF: 0.102 AC: 125489 AN: 1226468 Hom.: 10 AF XY: 0.102 AC XY: 62289 AN XY: 609708

Gnomad4 AFR exome AF: 0.176

Gnomad4 AMR exome AF: 0.0819

Gnomad4 ASJ exome AF: 0.105

Gnomad4 EAS exome AF: 0.126

Gnomad4 SAS exome AF: 0.0873

Gnomad4 FIN exome AF: 0.104

Gnomad4 NFE exome AF: 0.100

Gnomad4 OTH exome AF: 0.115

GnomAD4 genome AF: 0.0508 AC: 5793 AN: 113940 Hom.: 412 Cov.: 0 AF XY: 0.0517 AC XY: 2731 AN XY: 52840

Gnomad4 AFR AF: 0.171

Gnomad4 AMR AF: 0.0231

Gnomad4 ASJ AF: 0.00501

Gnomad4 EAS AF: 0.00367

Gnomad4 SAS AF: 0.00399

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.00325

Gnomad4 OTH AF: 0.0395

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 10, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not specified Benign:2

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	Al Jalila Children's Genomics Center, Al Jalila Childrens Speciality Hospital	Feb 11, 2020	- -

Catecholaminergic polymorphic ventricular tachycardia 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	May 04, 2016	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jun 14, 2017

- -

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;