rs141314684

Positions:

chr1-115705203-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_001232.4(CASQ2):c.928G>A(p.Asp310Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000513 in 1,611,510 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D310D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00052 ( 3 hom. )

Consequence

CASQ2
NM_001232.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:4

Conservation

PhyloP100: 5.81

Variant links:

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]

CASQ2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_001232.4

BP4

Computational evidence support a benign effect (MetaRNN=0.053823203).

BP6

Variant 1-115705203-C-T is Benign according to our data. Variant chr1-115705203-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 162810.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=3, Benign=1}. Variant chr1-115705203-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000523 (763/1459158) while in subpopulation MID AF= 0.00382 (22/5756). AF 95% confidence interval is 0.00259. There are 3 homozygotes in gnomad4_exome. There are 400 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CASQ2	NM_001232.4 linkuse as main transcript	c.928G>A	p.Asp310Asn	missense_variant	9/11	ENST00000261448.6	NP_001223.2	O14958-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CASQ2	ENST00000261448.6 linkuse as main transcript	c.928G>A	p.Asp310Asn	missense_variant	9/11	1	NM_001232.4	ENSP00000261448.5	O14958-1
CASQ2	ENST00000488931.2 linkuse as main transcript	n.*300G>A		non_coding_transcript_exon_variant	11/13	3		ENSP00000518226.1
CASQ2	ENST00000488931.2 linkuse as main transcript	n.*300G>A		3_prime_UTR_variant	11/13	3		ENSP00000518226.1

Frequencies

GnomAD3 genomes

AF:

0.000420

AC:

AN:

152234

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000828

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000470

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000700

AC:

176

AN:

251352

Hom.:

AF XY:

0.000766

AC XY:

104

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00457

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00154

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000634

Gnomad OTH exome

AF:

0.000978

GnomAD4 exome

AF:

0.000523

AC:

763

AN:

1459158

Hom.:

Cov.:

AF XY:

0.000551

AC XY:

400

AN XY:

726106

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00433

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00139

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000410

Gnomad4 OTH exome

AF:

0.000730

GnomAD4 genome

AF:

0.000420

AC:

AN:

152352

Hom.:

Cov.:

AF XY:

0.000443

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.0000721

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00461

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000829

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000470

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000891

Hom.:

Bravo

AF:

0.000389

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000634

AC:

EpiCase

AF:

0.000818

EpiControl

AF:

0.000771

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 29, 2015	The p.Asp310Asn variant in CASQ2 has been identified by our laboratory in 1 teen ager with DCM and in 1 teenager with DCM and LVNC. In addition, this variant has been identified in 0.1% (18/16512) of South Asian chromosomes and 0.08% (55/666 77) European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac. broadinstitute.org; dbSNP rs141314684). Computational prediction tools and conse rvation analysis do not provide strong support for or against an impact to the p rotein. In summary, the clinical significance of the p.Asp310Asn variant is unce rtain. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 06, 2022	Variant summary: CASQ2 c.928G>A (p.Asp310Asn) results in a conservative amino acid change located in the Calsequestrin, C-terminal TRX-fold domain (IPR041860) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00063 in 282758 control chromosomes, predominantly at a frequency of 0.0046 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in CASQ2 causing Catecholaminergic Polymorphic Ventricular Tachycardia phenotype (0.0016), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Ashkenazi Jewish origin. c.928G>A has been reported in the literature in individuals affected with Brugada syndrome, Sudden Death, QT syndrome and unknown arrhythmia as well as asymptomatic individuals (Behr_2015, Sanchez_2016, Celestino-Soper_2017, Landstrom_2017, Ng_2020). These reports do not provide unequivocal conclusions about association of the variant with Catecholaminergic Polymorphic Ventricular Tachycardia. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (n=4), likely benign (n=1) and benign (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

Catecholaminergic polymorphic ventricular tachycardia 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 08, 2018

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 19, 2024

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25691538, 28404607, 25351510, 30847666, 35932045, 36291626, 28361054, 32693635, 27930701) -

Cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 06, 2018

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 26, 2023

This alteration is classified as likely 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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.56

Eigen

Uncertain

0.28

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.027

MetaRNN

Benign

0.054

MetaSVM

Benign

-0.40

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-2.8

REVEL

Uncertain

0.39

Sift

Benign

0.12

Sift4G

Benign

0.14

Polyphen

0.31

Vest4

0.58

MVP

0.93

MPC

0.056

ClinPred

0.078

GERP RS

5.6

Varity_R

0.50

gMVP

0.86

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over