1-115725557-GAAAAAAAAAAAAAAA-GAAAAAAAAAAAAAA

Variant summary

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

The NM_001232.4(CASQ2):​c.738-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.028 ( 51 hom., cov: 0)
Exomes 𝑓: 0.13 ( 14 hom. )

Consequence

CASQ2
NM_001232.4 splice_region, intron

Scores

Not classified

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.516

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: Benign. The variant received -16 ACMG points.

BP6
Variant 1-115725557-GA-G is Benign according to our data. Variant chr1-115725557-GA-G is described in CliVar as Benign. Clinvar id is 522226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GA-G is described in CliVar as Benign. Clinvar id is 522226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GA-G is described in CliVar as Benign. Clinvar id is 522226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GA-G is described in CliVar as Benign. Clinvar id is 522226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GA-G is described in CliVar as Benign. Clinvar id is 522226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GA-G is described in CliVar as Benign. Clinvar id is 522226.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115725557-GA-G is described in CliVar as Benign. Clinvar id is 522226.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 = 0.0284 (3235/113944) while in subpopulation AFR AF = 0.0456 (1407/30828). AF 95% confidence interval is 0.0437. There are 51 homozygotes in GnomAd4. There are 1486 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
BS2
High Homozygotes in GnomAd4 at 51 AR,AD gene

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes
AF:
0.0284
AC:
3233
AN:
113974
Hom.:
51
Cov.:
0
show subpopulations
Gnomad AFR
AF:
0.0456
Gnomad AMI
AF:
0.00260
Gnomad AMR
AF:
0.0215
Gnomad ASJ
AF:
0.00669
Gnomad EAS
AF:
0.00523
Gnomad SAS
AF:
0.00973
Gnomad FIN
AF:
0.00624
Gnomad MID
AF:
0.0122
Gnomad NFE
AF:
0.0260
Gnomad OTH
AF:
0.0227
GnomAD4 exome
AF:
0.132
AC:
164324
AN:
1244766
Hom.:
14
Cov.:
0
AF XY:
0.128
AC XY:
79523
AN XY:
619174
show subpopulations
⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.
African (AFR)
AF:
0.0884
AC:
2424
AN:
27410
American (AMR)
AF:
0.0762
AC:
2344
AN:
30744
Ashkenazi Jewish (ASJ)
AF:
0.113
AC:
2476
AN:
21822
East Asian (EAS)
AF:
0.0952
AC:
3352
AN:
35192
South Asian (SAS)
AF:
0.0885
AC:
6105
AN:
68948
European-Finnish (FIN)
AF:
0.104
AC:
3738
AN:
35852
Middle Eastern (MID)
AF:
0.120
AC:
429
AN:
3566
European-Non Finnish (NFE)
AF:
0.141
AC:
136614
AN:
969550
Other (OTH)
AF:
0.132
AC:
6842
AN:
51682
⚠️ 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: 0.307
Heterozygous variant carriers
0
11492
22983
34475
45966
57458
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
5584
11168
16752
22336
27920
<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:
0.0284
AC:
3235
AN:
113944
Hom.:
51
Cov.:
0
AF XY:
0.0281
AC XY:
1486
AN XY:
52850
show subpopulations
African (AFR)
AF:
0.0456
AC:
1407
AN:
30828
American (AMR)
AF:
0.0215
AC:
221
AN:
10300
Ashkenazi Jewish (ASJ)
AF:
0.00669
AC:
20
AN:
2990
East Asian (EAS)
AF:
0.00525
AC:
20
AN:
3812
South Asian (SAS)
AF:
0.00951
AC:
31
AN:
3260
European-Finnish (FIN)
AF:
0.00624
AC:
22
AN:
3526
Middle Eastern (MID)
AF:
0.0134
AC:
3
AN:
224
European-Non Finnish (NFE)
AF:
0.0260
AC:
1474
AN:
56690
Other (OTH)
AF:
0.0226
AC:
35
AN:
1546
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.466
Heterozygous variant carriers
0
131
262
393
524
655
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
42
84
126
168
210
<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:
0.0322
Hom.:
284

ClinVar

Significance: Benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Catecholaminergic polymorphic ventricular tachycardia 2 Benign:2
Dec 08, 2016
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 11, 2023
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not specified Benign:1
Feb 16, 2025
Laboratory of Genetics, Children's Clinical University Hospital Latvia
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Cardiomyopathy Benign:1
Sep 06, 2019
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
Mar 03, 2015
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

CASQ2-related disorder Benign:1
Sep 09, 2019
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
PhyloP100
0.52
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs56889721; hg19: chr1-116268178; API