rs886039821
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001378183.1(PIEZO2):c.5227C>T(p.Arg1743Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,122 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001378183.1 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIEZO2 | NM_001378183.1 | c.5227C>T | p.Arg1743Ter | stop_gained | 38/56 | ENST00000674853.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIEZO2 | ENST00000674853.1 | c.5227C>T | p.Arg1743Ter | stop_gained | 38/56 | NM_001378183.1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 33
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1383202Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 682410
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152122Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74308
ClinVar
Submissions by phenotype
Arthrogryposis, distal, with impaired proprioception and touch Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | New York Genome Center | Jul 03, 2020 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 11, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jul 28, 2020 | The PIEZO2 c.5053C>T (p.Arg1685Ter) variant is a stop-gained variant that has been reported in one study, in which it is found in a compound heterozygous state in two unrelated individuals with distal arthrogryposis with impaired proprioception and touch (Chesler et al. 2016). The patients presented with congenital hip dysplasia, finger contractures, foot deformities, and progressive scoliosis and had a history of hypotonia, delayed head control, shallow breathing, and delayed walking. Both patients also had selective loss of touch perception and proprioception, leading to ataxia and dysmetria. The p.Arg1685Ter is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. In vitro functional studies showed that p.Arg1685Ter transfected cells had significantly reduced mechanically evoked current, and analysis of PIEZO2 RNA expression in patient cells implied the variant leads to nonsense-mediated decay (Chesler et al. 2016). Based on the collective evidence and application of the ACMG criteria, the p.Arg1685Ter variant is classified as pathogenic for distal arthrogryposis with impaired proprioception and touch. - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 22, 2019 | A nonsense variant that is likely pathogenic has been identified in the PIEZO2 gene. The R1685X variant has been previously reported in two unrelated individuals, each harboring a second PIEZO2 variant, with congenital hip dysplasia, finger contractures, foot deformities, severe progressive scoliosis, hypotonia, delayed walking, ataxia, selective loss of discriminative touch perception, and impaired fine motor skills (Chesler et al., 2016). Functional studies showed that R1685X transfected cells had channel currents above baseline noise only, compared to wild type, supporting loss of function (Chesler et al., 2016). The R1685X variant is not observed in large population cohorts (Lek et al., 2016). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. Therefore, this variant is likely pathogenic; however, the possibility that it is benign cannot be excluded. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 16, 2022 | This sequence change creates a premature translational stop signal (p.Arg1685*) in the PIEZO2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PIEZO2 are known to be pathogenic (PMID: 27653382, 27843126). 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: 265867). This premature translational stop signal has been observed in individuals with clinical features of autosomal recessive distal arthrogryposis (PMID: 27653382). This variant is not present in population databases (gnomAD no frequency). - |
PIEZO2-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 29, 2024 | Variant summary: PIEZO2 c.5053C>T (p.Arg1685X) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The frequency data for this variant in gnomAD is considered unreliable, as metrics indicate poor data quality at this position. c.5053C>T has been reported in the literature in two unrelated individuals affected with skeletal malformations, hypotonia, and impaired proprioception who were compound heterozygous with other pathogenic variants (Chesler_2016). This publication reports experimental evidence evaluating an impact on protein function, finding a loss of channel current in cells transfected with the variant protein. The following publication has been ascertained in the context of this evaluation (PMID: 27653382). ClinVar contains an entry for this variant (Variation ID: 265867). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at