1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_001232.4(CASQ2):c.738-11_738-5delTTTTTTT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00124 in 1,401,858 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0051 ( 6 hom., cov: 0)

Exomes 𝑓: 0.00091 ( 2 hom. )

Consequence

CASQ2
NM_001232.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 6.12

Publications

3 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: AD, AR Classification: DEFINITIVE, MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen
catecholaminergic polymorphic ventricular tachycardia 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, 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 -16 ACMG points.

BP6

Variant 1-115725557-GAAAAAAA-G is Benign according to our data. Variant chr1-115725557-GAAAAAAA-G is described in CliVar as Benign/Likely_benign. Clinvar id is 502421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAAAAAAA-G is described in CliVar as Benign/Likely_benign. Clinvar id is 502421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAAAAAAA-G is described in CliVar as Benign/Likely_benign. Clinvar id is 502421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAAAAAAA-G is described in CliVar as Benign/Likely_benign. Clinvar id is 502421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAAAAAAA-G is described in CliVar as Benign/Likely_benign. Clinvar id is 502421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAAAAAAA-G is described in CliVar as Benign/Likely_benign. Clinvar id is 502421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GAAAAAAA-G is described in CliVar as Benign/Likely_benign. Clinvar id is 502421.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00506 (577/114004) while in subpopulation AFR AF = 0.0163 (503/30844). AF 95% confidence interval is 0.0151. There are 6 homozygotes in GnomAd4. There are 295 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ2	NM_001232.4 link	c.738-11_738-5delTTTTTTT		splice_region_variant, intron_variant	Intron 6 of 10	ENST00000261448.6	NP_001223.2	O14958-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CASQ2	ENST00000261448.6 link	c.738-11_738-5delTTTTTTT		splice_region_variant, intron_variant	Intron 6 of 10	1	NM_001232.4	ENSP00000261448.5		O14958-1

Frequencies

GnomAD3 genomes

AF:

0.00503

AC:

574

AN:

114034

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00233

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00105

Gnomad SAS

AF:

0.00639

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000317

Gnomad OTH

AF:

0.00453

GnomAD4 exome

AF:

0.000907

AC:

1168

AN:

1287854

Hom.:

AF XY:

0.000988

AC XY:

634

AN XY:

641506

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0136

AC:

386

AN:

28294

American (AMR)

AF:

0.000849

AC:

AN:

31816

Ashkenazi Jewish (ASJ)

AF:

0.000176

AC:

AN:

22758

East Asian (EAS)

AF:

0.000713

AC:

AN:

36454

South Asian (SAS)

AF:

0.00518

AC:

376

AN:

72620

European-Finnish (FIN)

AF:

0.000162

AC:

AN:

37118

Middle Eastern (MID)

AF:

0.00190

AC:

AN:

3680

European-Non Finnish (NFE)

AF:

0.000257

AC:

257

AN:

1001654

Other (OTH)

AF:

0.00148

AC:

AN:

53460

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.334

Heterozygous variant carriers

129

194

258

323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00506

AC:

577

AN:

114004

Hom.:

Cov.:

AF XY:

0.00558

AC XY:

295

AN XY:

52884

show subpopulations

African (AFR)

AF:

0.0163

AC:

503

AN:

30844

American (AMR)

AF:

0.00233

AC:

AN:

10306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2992

East Asian (EAS)

AF:

0.00105

AC:

AN:

3814

South Asian (SAS)

AF:

0.00644

AC:

AN:

3260

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

224

European-Non Finnish (NFE)

AF:

0.000317

AC:

AN:

56720

Other (OTH)

AF:

0.00452

AC:

AN:

1548

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.569

Heterozygous variant carriers

109

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:

0.00

Hom.:

284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Jun 06, 2017

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 2

Benign:1

Apr 11, 2023

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1;C2677794:Catecholaminergic polymorphic ventricular tachycardia 2

Benign:1

Sep 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Catecholaminergic polymorphic ventricular tachycardia 1

Benign:1

Oct 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

6.1

Mutation Taster

=86/14

polymorphism

(source)

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over