chr8-76983824-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000318.3(PEX2):c.355C>T(p.Arg119Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000743 in 1,614,056 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R119R) has been classified as Likely benign.
Frequency
Consequence
NM_000318.3 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 |
---|---|---|---|---|---|---|---|
PEX2 | NM_000318.3 | c.355C>T | p.Arg119Ter | stop_gained | 4/4 | ENST00000357039.9 | |
PEX2 | NM_001079867.2 | c.355C>T | p.Arg119Ter | stop_gained | 3/3 | ||
PEX2 | NM_001172086.2 | c.355C>T | p.Arg119Ter | stop_gained | 5/5 | ||
PEX2 | NM_001172087.2 | c.355C>T | p.Arg119Ter | stop_gained | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX2 | ENST00000357039.9 | c.355C>T | p.Arg119Ter | stop_gained | 4/4 | 1 | NM_000318.3 | P1 | |
PEX2 | ENST00000522527.5 | c.355C>T | p.Arg119Ter | stop_gained | 3/3 | 1 | P1 | ||
PEX2 | ENST00000520103.5 | c.355C>T | p.Arg119Ter | stop_gained | 3/3 | 2 | P1 | ||
PEX2 | ENST00000518986.5 | c.355C>T | p.Arg119Ter | stop_gained | 3/3 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000855 AC: 13AN: 152072Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000143 AC: 36AN: 251402Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135868
GnomAD4 exome AF: 0.0000732 AC: 107AN: 1461864Hom.: 0 Cov.: 35 AF XY: 0.0000798 AC XY: 58AN XY: 727222
GnomAD4 genome AF: 0.0000854 AC: 13AN: 152192Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74404
ClinVar
Submissions by phenotype
Peroxisome biogenesis disorder 5A (Zellweger) Pathogenic:4
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 26, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Dec 26, 2019 | NM_000318.2(PEX2):c.355C>T(R119*) is classified as pathogenic in the context of peroxisome biogenesis disorder type 5. Sources cited for classification include the following: PMID 15542397, 1546315 and 14630978. Classification of NM_000318.2(PEX2):c.355C>T(R119*) is based on the following criteria: The variant causes a premature termination codon that is not expected to be targeted by nonsense-mediated mRNA decay; however, literature evidence strongly supports pathogenicity. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 07, 2024 | This sequence change creates a premature translational stop signal (p.Arg119*) in the PEX2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 187 amino acid(s) of the PEX2 protein. This variant is present in population databases (rs61752123, gnomAD 0.3%). This premature translational stop signal has been observed in individual(s) with Zellweger spectrum disorders (PMID: 1546315, 7681622, 9452066, 9585609, 10528859, 15542397, 21465523, 23430938). ClinVar contains an entry for this variant (Variation ID: 13704). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 27, 2023 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Jun 10, 2021 | - - |
Peroxisome biogenesis disorder 5B Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Aug 16, 2016 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2014 | - - |
Zellweger spectrum disorders Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Peroxisome biogenesis disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 31, 2017 | Variant summary: The PEX2 c.355C>T (p.Arg119X) variant results in a premature termination codon, predicted to cause a truncated or absent PEX2 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. One in silico tool predicts a damaging outcome for this variant. This variant was found in the large control database ExAC and control cohorts in the literature at a frequency of 0.0002708 (34/125548 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX2 variant (0.001118). Several publications have cited the variant in patients with diagnoses that are confirmed with standard biochemical tests. Additionally, a functional study demonstrated a lack of peroxisome formation via immunofluorescence in cultured fibroblasts of a patient who was homozygous for the variant of interest (Imamura_AJHG_1998). Furthermore, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Peroxisome biogenesis disorder 5B;C3553940:Peroxisome biogenesis disorder 5A (Zellweger) Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Jan 04, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at