1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAAA

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_001232.4(CASQ2):​c.738-9_738-5delTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00242 in 1,278,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 0)
Exomes 𝑓: 0.0024 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CASQ2
NM_001232.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:3

Conservation

PhyloP100: 1.72

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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP6
Variant 1-115725557-GAAAAA-G is Benign according to our data. Variant chr1-115725557-GAAAAA-G is described in CliVar as Benign. Clinvar id is 928920.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-GAAAAA-G is described in CliVar as Benign. Clinvar id is 928920.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-GAAAAA-G is described in CliVar as Benign. Clinvar id is 928920.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-GAAAAA-G is described in CliVar as Benign. Clinvar id is 928920.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-GAAAAA-G is described in CliVar as Benign. Clinvar id is 928920.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-GAAAAA-G is described in CliVar as Benign. Clinvar id is 928920.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-115725557-GAAAAA-G is described in CliVar as Benign. Clinvar id is 928920.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CASQ2NM_001232.4 linkc.738-9_738-5delTTTTT 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
CASQ2ENST00000261448.6 linkc.738-9_738-5delTTTTT splice_region_variant, intron_variant Intron 6 of 10 1 NM_001232.4 ENSP00000261448.5 O14958-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
114030
Hom.:
0
Cov.:
0
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:
0.00242
AC:
3095
AN:
1278340
Hom.:
0
AF XY:
0.00247
AC XY:
1574
AN XY:
636780
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.00528
AC:
148
AN:
28034
American (AMR)
AF:
0.00426
AC:
134
AN:
31482
Ashkenazi Jewish (ASJ)
AF:
0.00213
AC:
48
AN:
22588
East Asian (EAS)
AF:
0.00504
AC:
181
AN:
35902
South Asian (SAS)
AF:
0.00219
AC:
158
AN:
72252
European-Finnish (FIN)
AF:
0.00422
AC:
155
AN:
36718
Middle Eastern (MID)
AF:
0.00165
AC:
6
AN:
3640
European-Non Finnish (NFE)
AF:
0.00211
AC:
2100
AN:
994674
Other (OTH)
AF:
0.00311
AC:
165
AN:
53050
⚠️ 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: 0.274
Heterozygous variant carriers
0
333
666
1000
1333
1666
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
72
144
216
288
360
<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:
0
AN:
114000
Hom.:
0
Cov.:
0
AF XY:
0.00
AC XY:
0
AN XY:
52882
African (AFR)
AF:
0.00
AC:
0
AN:
30842
American (AMR)
AF:
0.00
AC:
0
AN:
10306
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
2992
East Asian (EAS)
AF:
0.00
AC:
0
AN:
3814
South Asian (SAS)
AF:
0.00
AC:
0
AN:
3260
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
3528
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
224
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
56720
Other (OTH)
AF:
0.00
AC:
0
AN:
1546
Alfa
AF:
0.0391
Hom.:
284

ClinVar

Significance: Benign
Submissions summary: Benign:3
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:3
-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Sep 17, 2019
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Variant summary: CASQ2 c.738-9_738-5delTTTTT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 179292 control chromosomes (gnomAD). However, the variant is located in a homopolymer region of 20 Ts, which is a highly polymorphic region. Therefore, suggesting the region is tolerable to changes in length of poly Ts. To our knowledge, no occurrence of c.738-9_738-5delTTTTT in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrence with another pathogenic variant has been observed in an internal LCA sample (PKP2 c.2197_2202delinsG , p.H733fsX8), providing supporting evidence for a benign role. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
1.7
Mutation Taster
=70/30
polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs56889721; hg19: chr1-116268178; API