chr8-76983806-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000357039.9(PEX2):c.373C>T(p.Arg125Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000143 in 1,613,902 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R125R) has been classified as Likely benign.
Frequency
Consequence
ENST00000357039.9 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 | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PEX2 | NM_000318.3 | c.373C>T | p.Arg125Ter | stop_gained | 4/4 | ENST00000357039.9 | NP_000309.2 | |
PEX2 | NM_001079867.2 | c.373C>T | p.Arg125Ter | stop_gained | 3/3 | NP_001073336.2 | ||
PEX2 | NM_001172086.2 | c.373C>T | p.Arg125Ter | stop_gained | 5/5 | NP_001165557.2 | ||
PEX2 | NM_001172087.2 | c.373C>T | p.Arg125Ter | stop_gained | 3/3 | NP_001165558.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PEX2 | ENST00000357039.9 | c.373C>T | p.Arg125Ter | stop_gained | 4/4 | 1 | NM_000318.3 | ENSP00000349543 | P1 | |
PEX2 | ENST00000522527.5 | c.373C>T | p.Arg125Ter | stop_gained | 3/3 | 1 | ENSP00000428638 | P1 | ||
PEX2 | ENST00000520103.5 | c.373C>T | p.Arg125Ter | stop_gained | 3/3 | 2 | ENSP00000428590 | P1 | ||
PEX2 | ENST00000518986.5 | c.373C>T | p.Arg125Ter | stop_gained | 3/3 | 3 | ENSP00000429304 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 152074Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251382Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135868
GnomAD4 exome AF: 0.0000144 AC: 21AN: 1461828Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8AN XY: 727202
GnomAD4 genome AF: 0.0000132 AC: 2AN: 152074Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74288
ClinVar
Submissions by phenotype
Peroxisome biogenesis disorder 5B;C3553940:Peroxisome biogenesis disorder 5A (Zellweger) Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Juno Genomics, Hangzhou Juno Genomics, Inc | - | PM2_Supporting+PVS1_Strong+PM3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 01, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 15, 2021 | - - |
Peroxisome biogenesis disorder 5A (Zellweger) Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 20, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 06, 2024 | This sequence change creates a premature translational stop signal (p.Arg125*) in the PEX2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 181 amino acid(s) of the PEX2 protein. This variant is present in population databases (rs61752124, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Zellweger syndrome (PMID: 9452066, 21465523). ClinVar contains an entry for this variant (Variation ID: 549898). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects PEX2 function (PMID: 10528859). This variant disrupts the C-terminus of the PEX2 protein. Other variant(s) that disrupt this region (p.Arg184Valfs*8, p.Trp223* p.Phe278Leufs*3, p.Ser289Lysfs*36) have been observed in individuals with PEX2-related conditions (PMID: 10652207, 14630978, 17041890). This suggests that this may be a clinically significant region of the protein. For these reasons, this variant has been classified as Pathogenic. - |
Zellweger spectrum disorders Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Mar 04, 2024 | Nonsense variant predicted to result in protein truncation, as the last 181 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; In vitro studies demonstrate the p.R125* variant has a deleterious effect on protein function with severely reduced PEX2 activity (PMID: 10528859); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17045664, 11330042, 21465523, 9375798, Vo2021[abstract], Ranganath2022[abstract], 21031596, 15542397, 9452066, 10528859, 31964843, 36198807) - |
Peroxisome biogenesis disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 04, 2018 | Variant summary: PEX2 c.373C>T (p.Arg125X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 8.2e-06 in 121346 control chromosomes. c.373C>T has been reported in the literature in individuals with biochemically confirmed Zellweger Syndrome . These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Peroxisome biogenesis disorder 5B Pathogenic:1
Pathogenic, no assertion criteria provided | research | Center of Excellence for Medical Genomics, Chulalongkorn University | Sep 08, 2002 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at