rs776874142
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_001232.4(CASQ2):c.783G>A(p.Trp261Ter) variant causes a stop gained, splice region change. The variant allele was found at a frequency of 0.00000311 in 1,609,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001232.4 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CASQ2 | NM_001232.4 | c.783G>A | p.Trp261Ter | stop_gained, splice_region_variant | 7/11 | ENST00000261448.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CASQ2 | ENST00000261448.6 | c.783G>A | p.Trp261Ter | stop_gained, splice_region_variant | 7/11 | 1 | NM_001232.4 | P1 | |
CASQ2 | ENST00000488931.2 | c.*155G>A | splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant | 9/13 | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.00000671 AC: 1AN: 149124Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250624Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135434
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460668Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 726650
GnomAD4 genome ? AF: 0.00000671 AC: 1AN: 149124Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 1AN XY: 72460
ClinVar
Submissions by phenotype
Catecholaminergic polymorphic ventricular tachycardia 2 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Center for Human Genetics, University of Leuven | Feb 09, 2017 | ACMG score likely pathogenic - |
Catecholaminergic polymorphic ventricular tachycardia 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 28, 2022 | This sequence change creates a premature translational stop signal (p.Trp261*) in the CASQ2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CASQ2 are known to be pathogenic (PMID: 12386154). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 427947). This premature translational stop signal has been observed in individual(s) with catecholaminergic polymorphic ventricular tachycardia (PMID: 32693635). This variant is present in population databases (rs776874142, gnomAD 0.004%). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at