Genetic Variant CASQ2:c.738-13_738-5delTTTTTTTTT (chr1-115725557-GAAAAAAAAA-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001232.4(CASQ2):c.738-13_738-5delTTTTTTTTT variant causes a splice region, intron change. The variant allele was found at a frequency of 0.000121 in 1,402,772 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000088 ( 1 hom., cov: 0)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

CASQ2
NM_001232.4 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.0000877

AC:

AN:

114030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000194

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00122

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000353

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000124

AC:

160

AN:

1288742

Hom.:

AF XY:

0.000120

AC XY:

AN XY:

641972

show subpopulations

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

African (AFR)

AF:

0.000740

AC:

AN:

28362

American (AMR)

AF:

0.0000943

AC:

AN:

31828

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22772

East Asian (EAS)

AF:

0.00

AC:

AN:

36486

South Asian (SAS)

AF:

0.000632

AC:

AN:

72756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37150

Middle Eastern (MID)

AF:

0.000272

AC:

AN:

3680

European-Non Finnish (NFE)

AF:

0.0000838

AC:

AN:

1002202

Other (OTH)

AF:

0.0000934

AC:

AN:

53506

⚠️ 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: 0.364

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

AF:

0.0000877

AC:

AN:

114030

Hom.:

Cov.:

AF XY:

0.0000946

AC XY:

AN XY:

52882

show subpopulations

African (AFR)

AF:

0.0000649

AC:

AN:

30806

American (AMR)

AF:

0.000194

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:

0.00122

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:

0.0000353

AC:

AN:

56732

Other (OTH)

AF:

0.00

AC:

AN:

1544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.494

Heterozygous variant carriers

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

Not reported in ClinVar

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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1-115725557-GAAAAAAAAAAAAAAA-GAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over