rs28730712

chr1-115702930-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001232.4(CASQ2):c.1005T>C(p.Asn335=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,613,282 control chromosomes in the GnomAD database, including 189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (88 hom., cov: 33)
  • Exomes 𝑓: 0.0023 (101 hom.)
• Consequence: CASQ2 NM_001232.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.605

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 1-115702930-A-G is Benign according to our data. Variant chr1-115702930-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 44152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115702930-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.605 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.064 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CASQ2	NM_001232.4	c.1005T>C	p.Asn335=	synonymous_variant	10/11	ENST00000261448.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CASQ2	ENST00000261448.6	c.1005T>C	p.Asn335=	synonymous_variant	10/11	1	NM_001232.4	P1
CASQ2	ENST00000488931.2	c.*377T>C		3_prime_UTR_variant, NMD_transcript_variant	12/13	3

Frequencies

GnomAD3 genomes AF: 0.0195 AC: 2964 AN: 152166 Hom.: 87 Cov.: 33

Gnomad AFR AF: 0.0660

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00858

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.0162

GnomAD3 exomes AF: 0.00531 AC: 1329 AN: 250068 Hom.: 44 AF XY: 0.00408 AC XY: 551 AN XY: 135182

Gnomad AFR exome AF: 0.0668

Gnomad AMR exome AF: 0.00342

Gnomad ASJ exome AF: 0.00489

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000263

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000636

Gnomad OTH exome AF: 0.00360

GnomAD4 exome AF: 0.00234 AC: 3412 AN: 1460998 Hom.: 101 Cov.: 30 AF XY: 0.00208 AC XY: 1512 AN XY: 726758

Gnomad4 AFR exome AF: 0.0689

Gnomad4 AMR exome AF: 0.00452

Gnomad4 ASJ exome AF: 0.00544

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000316

Gnomad4 OTH exome AF: 0.00543

GnomAD4 genome AF: 0.0195 AC: 2975 AN: 152284 Hom.: 88 Cov.: 33 AF XY: 0.0185 AC XY: 1380 AN XY: 74470

Gnomad4 AFR AF: 0.0661

Gnomad4 AMR AF: 0.00850

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00868 Hom.: 23

Bravo AF: 0.0223

Asia WGS AF: 0.00693 AC: 25 AN: 3478

EpiCase AF: 0.000981

EpiControl AF: 0.00130

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 2 Benign:4

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 06, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 22, 2012	6.0% (225/3738) Afr Amer chrom (ESP) -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Catecholaminergic polymorphic ventricular tachycardia Benign:2

Likely benign, no assertion criteria provided	clinical testing	Cohesion Phenomics	Sep 23, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -

not provided Benign:2

Likely 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	GeneDx	Mar 03, 2015	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jul 25, 2016

- -

Caudal regression sequence Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Catecholaminergic polymorphic ventricular tachycardia 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Neural tube defect Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 17, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	5.6
Dann	Benign	0.79

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: rs28730712; hg19: chr1-116245551;