rs375598471
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_001232.4(CASQ2):c.475G>T(p.Glu159Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000274 in 1,461,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )
Consequence
CASQ2
NM_001232.4 stop_gained
NM_001232.4 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 3.93
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 1-115738281-C-A is Pathogenic according to our data. Variant chr1-115738281-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 654552.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASQ2 | NM_001232.4 | c.475G>T | p.Glu159Ter | stop_gained | 4/11 | ENST00000261448.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASQ2 | ENST00000261448.6 | c.475G>T | p.Glu159Ter | stop_gained | 4/11 | 1 | NM_001232.4 | P1 | |
CASQ2 | ENST00000488931.2 | c.199G>T | p.Glu67Ter | stop_gained, NMD_transcript_variant | 5/13 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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Cov.:
32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251412Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135870
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461694Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 727158
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Feb 09, 2021 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CASQ2 are known to be pathogenic (PMID: 12386154). This variant has not been reported in the literature in individuals with CASQ2-related disease. This variant is present in population databases (rs375598471, ExAC 0.003%). This sequence change creates a premature translational stop signal (p.Glu159*) in the CASQ2 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;D
Vest4
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at