rs749956542

Positions:

chr8-76983397-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_000318.3(PEX2):c.782A>G(p.His261Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000744 in 1,613,966 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 Conflicting classifications of pathogenicity (no stars).

Frequency

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

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

PEX2
NM_000318.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:4

Conservation

PhyloP100: 7.49

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 Likely_pathogenic. Variant got 8 ACMG points.

PM1

In a binding_site (size 0) in uniprot entity PEX2_HUMAN

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PEX2	NM_000318.3 linkuse as main transcript	c.782A>G	p.His261Arg	missense_variant	4/4	ENST00000357039.9	NP_000309.2
PEX2	NM_001079867.2 linkuse as main transcript	c.782A>G	p.His261Arg	missense_variant	3/3		NP_001073336.2
PEX2	NM_001172086.2 linkuse as main transcript	c.782A>G	p.His261Arg	missense_variant	5/5		NP_001165557.2
PEX2	NM_001172087.2 linkuse as main transcript	c.782A>G	p.His261Arg	missense_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.782A>G	p.His261Arg	missense_variant	4/4	1	NM_000318.3	ENSP00000349543	P1
PEX2	ENST00000522527.5 linkuse as main transcript	c.782A>G	p.His261Arg	missense_variant	3/3	1		ENSP00000428638	P1
PEX2	ENST00000520103.5 linkuse as main transcript	c.782A>G	p.His261Arg	missense_variant	3/3	2		ENSP00000428590	P1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152168

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:

0.000478

GnomAD3 exomes

AF:

0.0000199

AC:

AN:

251300

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000684

AC:

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

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:

0.00000360

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74330

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:

0.000478

Bravo

AF:

0.0000189

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Peroxisome biogenesis disorder 5B;C3553940:Peroxisome biogenesis disorder 5A (Zellweger)

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 12, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 18, 2018	- -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

Dec 21, 2022

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

May 28, 2022

Variant summary: PEX2 c.782A>G (p.His261Arg) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain (IPR001841) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 251300 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.782A>G has been reported in the literature as a non-informative genotype (second allele not specified) in at-least one individual affected with Zellweger Syndrome (example, Ebberink_2011). These report(s) do not provide unequivocal conclusions about association of the variant with Zellweger Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Peroxisome biogenesis disorder 5A (Zellweger)

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 13, 2022

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 261 of the PEX2 protein (p.His261Arg). This variant is present in population databases (rs749956542, gnomAD 0.01%). This missense change has been observed in individual(s) with clinical features of Zellweger syndrome spectrum (PMID: 21031596). ClinVar contains an entry for this variant (Variation ID: 557949). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

D;D;D

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

.;.;D

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.4

M;M;M

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-7.9

D;D;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.97

MutPred

0.94

Loss of catalytic residue at F263 (P = 0.2085);Loss of catalytic residue at F263 (P = 0.2085);Loss of catalytic residue at F263 (P = 0.2085);

MVP

0.99

ClinPred

0.99

GERP RS

5.3

Varity_R

0.97

gMVP

0.96

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