rs764771123

Positions:

chr8-76983833-ACCACCTG-A

Variant summary

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

The ENST00000357039.9(PEX2):c.339_345del(p.Arg114Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000211 in 1,613,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

PEX2
ENST00000357039.9 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

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 23 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-76983833-ACCACCTG-A is Pathogenic according to our data. Variant chr8-76983833-ACCACCTG-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 287499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PEX2	NM_000318.3 linkuse as main transcript	c.339_345del	p.Arg114Ter	frameshift_variant	4/4	ENST00000357039.9	NP_000309.2
PEX2	NM_001079867.2 linkuse as main transcript	c.339_345del	p.Arg114Ter	frameshift_variant	3/3		NP_001073336.2
PEX2	NM_001172086.2 linkuse as main transcript	c.339_345del	p.Arg114Ter	frameshift_variant	5/5		NP_001165557.2
PEX2	NM_001172087.2 linkuse as main transcript	c.339_345del	p.Arg114Ter	frameshift_variant	3/3		NP_001165558.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
PEX2	ENST00000357039.9 linkuse as main transcript	c.339_345del	p.Arg114Ter	frameshift_variant	4/4	1	NM_000318.3	ENSP00000349543	P1
PEX2	ENST00000522527.5 linkuse as main transcript	c.339_345del	p.Arg114Ter	frameshift_variant	3/3	1		ENSP00000428638	P1
PEX2	ENST00000518986.5 linkuse as main transcript	c.339_345del	p.Arg114Ter	frameshift_variant	3/3	3		ENSP00000429304
PEX2	ENST00000520103.5 linkuse as main transcript	c.339_345del	p.Arg114Ter	frameshift_variant	3/3	2		ENSP00000428590	P1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152070

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000318

AC:

AN:

251426

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135886

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:

0.0000704

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461880

Hom.:

AF XY:

0.0000261

AC XY:

AN XY:

727238

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:

0.0000297

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152070

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74272

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 5A (Zellweger)

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Jan 01, 2016	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP5. -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 20, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 16, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 08, 2023	This sequence change creates a premature translational stop signal (p.Arg114) in the PEX2 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 192 amino acid(s) of the PEX2 protein. This variant is present in population databases (rs764771123, gnomAD 0.008%). This premature translational stop signal has been observed in individual(s) with Zellweger syndrome (PMID: 21031596). ClinVar contains an entry for this variant (Variation ID: 287499). This variant disrupts a region of the PEX2 protein in which other variant(s) (p.Arg119) have been determined to be pathogenic (PMID: 1546315, 9452066, 9585609, 10528859). 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. -

Peroxisome biogenesis disorder 5B

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 26, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Aug 16, 2016	- -

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

Apr 28, 2017

Variant summary: The PEX2 c.339_345delCAGGTGG (p.Arg114fs) 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. LCA has classified another downstream truncation variant, c.355C>T (p.Arg119X) as pathogenic. This variant was found in 3/121458 control chromosomes at a frequency of 0.0000247, which does not exceed the estimated maximal expected allele frequency of a pathogenic PEX2 variant (0.001118). A publication has cited the variant in two individuals, one homozygous and one assumed compound heterozygous, diagnosed with ZS (Ebberink_2010). In addition, multiple clinical diagnostic laboratories classified this variant as "likely pathogenic/pathogenic. Taken together, this variant is classified as "Pathogenic." -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 11, 2016

- -

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