rs786205272

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001232.4(CASQ2):c.1185_1187delCGA(p.Asp396del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00613 in 1,600,538 control chromosomes in the GnomAD database, including 55 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. D395D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0039 ( 7 hom., cov: 31)

Exomes 𝑓: 0.0064 ( 48 hom. )

Consequence

CASQ2
NM_001232.4 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:14

Conservation

PhyloP100: 2.40

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

catecholaminergic polymorphic ventricular tachycardia
Inheritance: AR, AD Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
catecholaminergic polymorphic ventricular tachycardia 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Genomics England PanelApp
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

CASQ2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001232.4

BP6

Variant 1-115701253-ATCG-A is Benign according to our data. Variant chr1-115701253-ATCG-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44158.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00388 (591/152222) while in subpopulation NFE AF = 0.00628 (427/68006). AF 95% confidence interval is 0.00579. There are 7 homozygotes in GnomAd4. There are 269 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001232.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CASQ2	NM_001232.4	MANE Select	c.1185_1187delCGA	p.Asp396del	disruptive_inframe_deletion	Exon 11 of 11	NP_001223.2	O14958-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CASQ2	ENST00000261448.6	TSL:1 MANE Select	c.1185_1187delCGA	p.Asp396del	disruptive_inframe_deletion	Exon 11 of 11	ENSP00000261448.5	O14958-1
CASQ2	ENST00000713711.1		c.1326_1328delCGA	p.Asp443del	disruptive_inframe_deletion	Exon 12 of 12	ENSP00000519014.1	A0AAQ5BGS1
CASQ2	ENST00000874189.1		c.1110_1112delCGA	p.Asp371del	disruptive_inframe_deletion	Exon 10 of 10	ENSP00000544248.1

Frequencies

GnomAD3 genomes

AF:

0.00389

AC:

591

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00125

Gnomad FIN

AF:

0.00565

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00628

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00464

AC:

1161

AN:

250482

AF XY:

0.00426

show subpopulations

Gnomad AFR exome

AF:

0.00173

Gnomad AMR exome

AF:

0.00154

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00665

Gnomad NFE exome

AF:

0.00784

Gnomad OTH exome

AF:

0.00376

GnomAD4 exome

AF:

0.00637

AC:

9221

AN:

1448316

Hom.:

AF XY:

0.00608

AC XY:

4386

AN XY:

720998

show subpopulations

African (AFR)

AF:

0.000936

AC:

AN:

33132

American (AMR)

AF:

0.00170

AC:

AN:

44626

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26022

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39634

South Asian (SAS)

AF:

0.000874

AC:

AN:

85784

European-Finnish (FIN)

AF:

0.00675

AC:

359

AN:

53172

Middle Eastern (MID)

AF:

0.000175

AC:

AN:

5714

European-Non Finnish (NFE)

AF:

0.00764

AC:

8404

AN:

1100312

Other (OTH)

AF:

0.00456

AC:

273

AN:

59920

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

433

866

1298

1731

2164

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

322

644

966

1288

1610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00388

AC:

591

AN:

152222

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

269

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.00144

AC:

AN:

41530

American (AMR)

AF:

0.00190

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00125

AC:

AN:

4808

European-Finnish (FIN)

AF:

0.00565

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00628

AC:

427

AN:

68006

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

122

152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00356

Hom.:

Bravo

AF:

0.00361

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00464

EpiControl

AF:

0.00500

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (5)

Catecholaminergic polymorphic ventricular tachycardia 2 (3)

Cardiomyopathy (1)

Cardiovascular phenotype (1)

Catecholaminergic polymorphic ventricular tachycardia 1 (1)

Primary dilated cardiomyopathy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.4

Mutation Taster

=64/36

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over