NM_001232.4:c.738-13_738-5dupTTTTTTTTT

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_001232.4(CASQ2):c.738-13_738-5dupTTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.000026 ( 2 hom. )

Failed GnomAD Quality Control

Consequence

CASQ2
NM_001232.4 splice_region, intron

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.516

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP6

Variant 1-115725557-G-GAAAAAAAAA is Benign according to our data. Variant chr1-115725557-G-GAAAAAAAAA is described in CliVar as Likely_benign. Clinvar id is 1758619.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-G-GAAAAAAAAA is described in CliVar as Likely_benign. Clinvar id is 1758619.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-G-GAAAAAAAAA is described in CliVar as Likely_benign. Clinvar id is 1758619.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-G-GAAAAAAAAA is described in CliVar as Likely_benign. Clinvar id is 1758619.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-G-GAAAAAAAAA is described in CliVar as Likely_benign. Clinvar id is 1758619.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-G-GAAAAAAAAA is described in CliVar as Likely_benign. Clinvar id is 1758619.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-G-GAAAAAAAAA is described in CliVar as Likely_benign. Clinvar id is 1758619.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CASQ2	NM_001232.4 link	c.738-13_738-5dupTTTTTTTTT		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.738-5_738-4insTTTTTTTTT		splice_region_variant, intron_variant	Intron 6 of 10	1	NM_001232.4	ENSP00000261448.5		O14958-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

114030

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000256

AC:

AN:

1288804

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

641994

show subpopulations

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

African (AFR)

AF:

0.0000705

AC:

AN:

28374

American (AMR)

AF:

0.000126

AC:

AN:

31830

Ashkenazi Jewish (ASJ)

AF:

0.0000439

AC:

AN:

22774

East Asian (EAS)

AF:

0.000137

AC:

AN:

36484

South Asian (SAS)

AF:

0.0000550

AC:

AN:

72756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37158

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3680

European-Non Finnish (NFE)

AF:

0.0000150

AC:

AN:

1002244

Other (OTH)

AF:

0.0000374

AC:

AN:

53504

⚠️ 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: 0.320

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

114030

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

52882

African (AFR)

AF:

0.00

AC:

AN:

30806

American (AMR)

AF:

0.00

AC:

AN:

10302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2992

East Asian (EAS)

AF:

0.00

AC:

AN:

3824

South Asian (SAS)

AF:

0.00

AC:

AN:

3288

European-Finnish (FIN)

AF:

0.00

AC:

AN:

3528

Middle Eastern (MID)

AF:

0.00

AC:

AN:

246

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

56732

Other (OTH)

AF:

0.00

AC:

AN:

1544

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Cardiovascular phenotype

Benign:1

May 03, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

PhyloP100

0.52

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over