rs61752122

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000318.3(PEX2):c.279_283del(p.Arg94SerfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,614,046 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

PEX2
NM_000318.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 8.51

Variant links:

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]

PEX2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 29 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-76983895-TATCTC-T is Pathogenic according to our data. Variant chr8-76983895-TATCTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 139588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PEX2	NM_000318.3 linkuse as main transcript	c.279_283del	p.Arg94SerfsTer5	frameshift_variant	4/4	ENST00000357039.9
PEX2	NM_001079867.2 linkuse as main transcript	c.279_283del	p.Arg94SerfsTer5	frameshift_variant	3/3
PEX2	NM_001172086.2 linkuse as main transcript	c.279_283del	p.Arg94SerfsTer5	frameshift_variant	5/5
PEX2	NM_001172087.2 linkuse as main transcript	c.279_283del	p.Arg94SerfsTer5	frameshift_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PEX2	ENST00000357039.9 linkuse as main transcript	c.279_283del	p.Arg94SerfsTer5	frameshift_variant	4/4	1	NM_000318.3	P1
PEX2	ENST00000522527.5 linkuse as main transcript	c.279_283del	p.Arg94SerfsTer5	frameshift_variant	3/3	1		P1
PEX2	ENST00000518986.5 linkuse as main transcript	c.279_283del	p.Arg94SerfsTer5	frameshift_variant	3/3	3
PEX2	ENST00000520103.5 linkuse as main transcript	c.279_283del	p.Arg94SerfsTer5	frameshift_variant	3/3	2		P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251350

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461880

Hom.:

AF XY:

0.00000963

AC XY:

AN XY:

727236

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74326

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 5A (Zellweger)

Pathogenic:3

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 24, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	This sequence change creates a premature translational stop signal (p.Arg94Serfs5) in the PEX2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 212 amino acid(s) of the PEX2 protein. This variant is present in population databases (rs61752122, gnomAD 0.003%). This premature translational stop signal has been observed in individuals with Zellweger syndrome spectrum (PMID: 21031596). ClinVar contains an entry for this variant (Variation ID: 139588). This variant disrupts a region of the PEX2 protein in which other variant(s) (p.Arg184Valfs8) have been determined to be pathogenic (PMID: 10652207; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. 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

- -

Peroxisome biogenesis disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

May 03, 2018

Variant summary: PEX2 c.279_283delGAGAT (p.Arg94SerfsX5) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.339_345delCAGGTGG (p.Arg114fsX1), c.355C>T (p.Arg119X)). The variant allele was found at a frequency of 1.6e-05 in 246158 control chromosomes. This frequency is not higher than expected for a pathogenic variant in PEX2 causing Zellweger Syndrome (1.6e-05 vs 0.0011), allowing no conclusion about variant significance. The variant, c.279_283delGAGAT, has been reported in the literature in at least two homozygous individuals and a compound heterozygous individual affected with Zellweger Syndrome (Gootjes 2004, Ebberink_2011). Gootjes et al. also reported experimental evidence evaluating an impact on protein function, demonstrating an absence of peroxisomes and severely decreased peroxisomal enzyme activities in patient fibroblasts. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over