rs61752123

chr8-76983824-G-Achr8-76983824-G-Cchr8-76983824-G-T

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

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000073 ( 0 hom. )

Consequence

PEX2
NM_000318.3 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 2.32

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 21 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-76983824-G-A is Pathogenic according to our data. Variant chr8-76983824-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 13704.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-76983824-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
PEX2	NM_000318.3 linkuse as main transcript	c.355C>T	p.Arg119Ter	stop_gained	4/4	ENST00000357039.9
PEX2	NM_001079867.2 linkuse as main transcript	c.355C>T	p.Arg119Ter	stop_gained	3/3
PEX2	NM_001172086.2 linkuse as main transcript	c.355C>T	p.Arg119Ter	stop_gained	5/5
PEX2	NM_001172087.2 linkuse as main transcript	c.355C>T	p.Arg119Ter	stop_gained	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
PEX2	ENST00000357039.9 linkuse as main transcript	c.355C>T	p.Arg119Ter	stop_gained	4/4	1	NM_000318.3	P1
PEX2	ENST00000522527.5 linkuse as main transcript	c.355C>T	p.Arg119Ter	stop_gained	3/3	1		P1
PEX2	ENST00000520103.5 linkuse as main transcript	c.355C>T	p.Arg119Ter	stop_gained	3/3	2		P1
PEX2	ENST00000518986.5 linkuse as main transcript	c.355C>T	p.Arg119Ter	stop_gained	3/3	3

Frequencies

GnomAD3 genomes

AF:

0.0000855

AC:

AN:

152072

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000143

AC:

AN:

251402

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00238

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.0000732

AC:

107

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000798

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00222

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.000182

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.0000869

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 5A (Zellweger)

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 20, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 01, 2014	- -
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. -
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. -

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	literature only	OMIM	Apr 01, 2014	- -
Pathogenic, no assertion criteria provided	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

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.30

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Benign

0.19

Eigen_PC

Benign

-0.11

FATHMM_MKL

Uncertain

0.82

MutationTaster

Benign

1.0

A;A;A;A

Vest4

0.83

GERP RS

-3.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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