8-76983431-A-G

Position:

chr8-76983431-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000318.3(PEX2):c.748T>C(p.Trp250Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00941 in 1,614,098 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0057 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0098 ( 104 hom. )

Consequence

PEX2
NM_000318.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:13

Conservation

PhyloP100: 8.73

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 Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015028745).

BP6

Variant 8-76983431-A-G is Benign according to our data. Variant chr8-76983431-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 129885.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Benign=2, Uncertain_significance=1}. Variant chr8-76983431-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00566 (861/152244) while in subpopulation NFE AF= 0.0101 (690/68008). AF 95% confidence interval is 0.00952. There are 3 homozygotes in gnomad4. There are 372 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
PEX2	NM_000318.3 linkuse as main transcript	c.748T>C	p.Trp250Arg	missense_variant	4/4	ENST00000357039.9	NP_000309.2
PEX2	NM_001079867.2 linkuse as main transcript	c.748T>C	p.Trp250Arg	missense_variant	3/3		NP_001073336.2
PEX2	NM_001172086.2 linkuse as main transcript	c.748T>C	p.Trp250Arg	missense_variant	5/5		NP_001165557.2
PEX2	NM_001172087.2 linkuse as main transcript	c.748T>C	p.Trp250Arg	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.748T>C	p.Trp250Arg	missense_variant	4/4	1	NM_000318.3	ENSP00000349543	P1
PEX2	ENST00000522527.5 linkuse as main transcript	c.748T>C	p.Trp250Arg	missense_variant	3/3	1		ENSP00000428638	P1
PEX2	ENST00000520103.5 linkuse as main transcript	c.748T>C	p.Trp250Arg	missense_variant	3/3	2		ENSP00000428590	P1

Frequencies

GnomAD3 genomes

AF:

0.00566

AC:

861

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00210

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00526

AC:

1321

AN:

251326

Hom.:

AF XY:

0.00526

AC XY:

714

AN XY:

135828

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00377

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00170

Gnomad FIN exome

AF:

0.00277

Gnomad NFE exome

AF:

0.00935

Gnomad OTH exome

AF:

0.00554

GnomAD4 exome

AF:

0.00980

AC:

14320

AN:

1461854

Hom.:

104

Cov.:

AF XY:

0.00950

AC XY:

6910

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.00149

Gnomad4 AMR exome

AF:

0.00179

Gnomad4 ASJ exome

AF:

0.00478

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00198

Gnomad4 FIN exome

AF:

0.00245

Gnomad4 NFE exome

AF:

0.0119

Gnomad4 OTH exome

AF:

0.00906

GnomAD4 genome

AF:

0.00566

AC:

861

AN:

152244

Hom.:

Cov.:

AF XY:

0.00500

AC XY:

372

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.00185

Gnomad4 AMR

AF:

0.00209

Gnomad4 ASJ

AF:

0.00691

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00245

Gnomad4 NFE

AF:

0.0101

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00808

Hom.:

Bravo

AF:

0.00596

TwinsUK

AF:

0.0105

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0119

AC:

102

ExAC

AF:

0.00499

AC:

606

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0105

EpiControl

AF:

0.0101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:13

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 29, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	PEX2: BS2 -

Peroxisome biogenesis disorder 5A (Zellweger)

Uncertain:1Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 24, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 19, 2016	- -

Zellweger spectrum disorders

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 15, 2019

- -

Peroxisome biogenesis disorder 5B

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Peroxisome biogenesis disorder 1A (Zellweger)

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.10

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;T;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.51

.;.;T

MetaRNN

Benign

0.015

T;T;T

MetaSVM

Uncertain

-0.055

MutationAssessor

Benign

1.4

L;L;L

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.6

D;D;D

REVEL

Uncertain

0.55

Sift

Benign

0.72

T;T;T

Sift4G

Benign

0.77

T;T;T

Polyphen

1.0

D;D;D

Vest4

0.82

MutPred

0.68

Gain of disorder (P = 0.0331);Gain of disorder (P = 0.0331);Gain of disorder (P = 0.0331);

MVP

0.90

ClinPred

0.036

GERP RS

5.2

Varity_R

0.59

gMVP

0.73

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