1-115701291-TATCATC-TATCATCATC
Position:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000261448.6(CASQ2):c.1149_1150insGAT(p.Asp383dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000521 in 1,594,326 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000049 ( 1 hom. )
Consequence
CASQ2
ENST00000261448.6 inframe_insertion
ENST00000261448.6 inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -5.01
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CASQ2 | NM_001232.4 | c.1149_1150insGAT | p.Asp383dup | inframe_insertion | 11/11 | ENST00000261448.6 | NP_001223.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CASQ2 | ENST00000261448.6 | c.1149_1150insGAT | p.Asp383dup | inframe_insertion | 11/11 | 1 | NM_001232.4 | ENSP00000261448 | P1 | |
CASQ2 | ENST00000488931.2 | c.*521_*522insGAT | 3_prime_UTR_variant, NMD_transcript_variant | 13/13 | 3 | ENSP00000518226 |
Frequencies
GnomAD3 genomes AF: 0.0000855 AC: 13AN: 152086Hom.: 0 Cov.: 32
GnomAD3 genomes
AF:
AC:
13
AN:
152086
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000560 AC: 14AN: 250136Hom.: 0 AF XY: 0.0000518 AC XY: 7AN XY: 135164
GnomAD3 exomes
AF:
AC:
14
AN:
250136
Hom.:
AF XY:
AC XY:
7
AN XY:
135164
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000485 AC: 70AN: 1442122Hom.: 1 Cov.: 26 AF XY: 0.0000473 AC XY: 34AN XY: 718686
GnomAD4 exome
AF:
AC:
70
AN:
1442122
Hom.:
Cov.:
26
AF XY:
AC XY:
34
AN XY:
718686
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74404
GnomAD4 genome
AF:
AC:
13
AN:
152204
Hom.:
Cov.:
32
AF XY:
AC XY:
6
AN XY:
74404
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Eurofins Ntd Llc (ga) | Feb 06, 2014 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 28, 2022 | Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In-frame duplication of 1 amino acids in a repetitive region with no known function - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 14, 2014 | The Asp378[7] variant in CASQ2 has not been previously reported in individuals w ith cardiomyopathy. Data from large population studies is insufficient to assess the frequency of this variant. This variant results in the addition of a single aspartic acid (Asp) in a poly aspartic acid stretch, which does not alter the r emainder of the protein. It is unclear if this addition impacts the protein. A d eletion (Asp378[5]) in this same string of residues has been identified by our l aboratory in 2 individuals with HCM, one of whom carried a likely pathogenic var iant in another gene (LMM unpublished data) and is listed in dbSNP (rs72554069) with limited frequency information. At this time, additional information is need ed to fully assess the clinical significance of the Asp378[7] variant. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Nov 14, 2017 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1;C2677794:Catecholaminergic polymorphic ventricular tachycardia 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 05, 2021 | - - |
Catecholaminergic polymorphic ventricular tachycardia 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 09, 2022 | This variant, c.1147_1149dup, results in the insertion of 1 amino acid(s) of the CASQ2 protein (p.Asp383dup), but otherwise preserves the integrity of the reading frame. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with CASQ2-related conditions. ClinVar contains an entry for this variant (Variation ID: 179599). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 15, 2021 | 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:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at