rs61752119
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate
The NM_000318.3(PEX2):c.163G>A(p.Glu55Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,570 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 (★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
PEX2
NM_000318.3 missense
NM_000318.3 missense
Scores
13
4
1
Clinical Significance
Conservation
PhyloP100: 7.57
Genes affected
PEX2 (HGNC:9717): (peroxisomal biogenesis factor 2) This gene encodes an integral peroxisomal membrane protein required for peroxisome biogenesis. The protein is thought to be involved in peroxisomal matrix protein import. Mutations in this gene result in one form of Zellweger syndrome and infantile Refsum disease. Alternative splicing results in multiple transcript variants encoding the same protein. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.984
PP5
?
Variant 8-76984016-C-T is Pathogenic according to our data. Variant chr8-76984016-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13705.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PEX2 | NM_000318.3 | c.163G>A | p.Glu55Lys | missense_variant | 4/4 | ENST00000357039.9 | |
PEX2 | NM_001079867.2 | c.163G>A | p.Glu55Lys | missense_variant | 3/3 | ||
PEX2 | NM_001172086.2 | c.163G>A | p.Glu55Lys | missense_variant | 5/5 | ||
PEX2 | NM_001172087.2 | c.163G>A | p.Glu55Lys | missense_variant | 3/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PEX2 | ENST00000357039.9 | c.163G>A | p.Glu55Lys | missense_variant | 4/4 | 1 | NM_000318.3 | P1 | |
PEX2 | ENST00000522527.5 | c.163G>A | p.Glu55Lys | missense_variant | 3/3 | 1 | P1 | ||
PEX2 | ENST00000520103.5 | c.163G>A | p.Glu55Lys | missense_variant | 3/3 | 2 | P1 | ||
PEX2 | ENST00000518986.5 | c.163G>A | p.Glu55Lys | missense_variant | 3/3 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461570Hom.: 0 Cov.: 35 AF XY: 0.0000151 AC XY: 11AN XY: 727046
GnomAD4 exome
AF:
AC:
30
AN:
1461570
Hom.:
Cov.:
35
AF XY:
AC XY:
11
AN XY:
727046
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Peroxisome biogenesis disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 27, 2023 | Variant summary: PEX2 c.163G>A (p.Glu55Lys) results in a conservative amino acid change to a highly conserved residue (HGMD) located in the Pex, N-terminal (IPR006845) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251214 control chromosomes (gnomAD). c.163G>A has been reported in the literature in an individual affected with Refsum disease who was compound heterozygous with a pathogenic variant (Imamura_1998, Shimozawa_1999). These data suggest the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that cells expressing the variant protein showed partially reduced enzymatic activity and recapitulated the catalase-less persoxisomes seen in patient cells (Fujiwara_2000, Shimozawa_1999). The following publications have been ascertained in the context of this evaluation (PMID: 9585609, 10528859, 10960480). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Peroxisome biogenesis disorder 5B Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 1999 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M;M;.
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;D;.
Polyphen
D;D;D;.
Vest4
MutPred
Gain of MoRF binding (P = 0.0092);Gain of MoRF binding (P = 0.0092);Gain of MoRF binding (P = 0.0092);Gain of MoRF binding (P = 0.0092);
MVP
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at