8-76984088-G-C

Variant names:

• chr8-76984088-G-C
• rs149287302
• NM_000318.3:c.91C>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000318.3(PEX2):​c.91C>G​(p.Gln31Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,612,476 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q31P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (14 hom.)
• Consequence: PEX2 NM_000318.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:9
• Conservation: PhyloP100: 7.64
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 5A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
• peroxisome biogenesis disorder 5B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012903988).
• BP6: Variant 8-76984088-G-C is Benign according to our data. Variant chr8-76984088-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92838.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000318.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX2	NM_000318.3	MANE Select	c.91C>G	p.Gln31Glu	missense	Exon 4 of 4	NP_000309.2
	PEX2	NM_001079867.2		c.91C>G	p.Gln31Glu	missense	Exon 3 of 3	NP_001073336.2
	PEX2	NM_001172086.2		c.91C>G	p.Gln31Glu	missense	Exon 5 of 5	NP_001165557.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX2	ENST00000357039.9	TSL:1 MANE Select	c.91C>G	p.Gln31Glu	missense	Exon 4 of 4	ENSP00000349543.4
	PEX2	ENST00000522527.5	TSL:1	c.91C>G	p.Gln31Glu	missense	Exon 3 of 3	ENSP00000428638.1
	PEX2	ENST00000520103.5	TSL:2	c.91C>G	p.Gln31Glu	missense	Exon 3 of 3	ENSP00000428590.1

Frequencies

GnomAD3 genomes AF: 0.00181 AC: 276 AN: 152098 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0161

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00109

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00250 AC: 626 AN: 250288 AF XY: 0.00258

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000553

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0162

Gnomad NFE exome AF: 0.00212

Gnomad OTH exome AF: 0.00263

GnomAD4 exome AF: 0.00155 AC: 2266 AN: 1460260 Hom.: 14 Cov.: 35 AF XY: 0.00150 AC XY: 1093 AN XY: 726314

African (AFR) AF: 0.0000600 AC: 2 AN: 33356

American (AMR) AF: 0.000629 AC: 28 AN: 44528

Ashkenazi Jewish (ASJ) AF: 0.0000384 AC: 1 AN: 26012

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.0000929 AC: 8 AN: 86074

European-Finnish (FIN) AF: 0.0168 AC: 894 AN: 53366

Middle Eastern (MID) AF: 0.00243 AC: 14 AN: 5752

European-Non Finnish (NFE) AF: 0.00112 AC: 1242 AN: 1111192

Other (OTH) AF: 0.00128 AC: 77 AN: 60292

GnomAD4 genome AF: 0.00181 AC: 276 AN: 152216 Hom.: 3 Cov.: 32 AF XY: 0.00232 AC XY: 173 AN XY: 74420

African (AFR) AF: 0.0000722 AC: 3 AN: 41532

American (AMR) AF: 0.00124 AC: 19 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.0161 AC: 171 AN: 10598

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00109 AC: 74 AN: 68016

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000884

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.00236 AC: 287

EpiCase AF: 0.00120

EpiControl AF: 0.00184

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Apr 16, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PEX2: BS2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Peroxisome biogenesis disorder 5A (Zellweger) Uncertain:1 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Peroxisome biogenesis disorder 5B;C3553940:Peroxisome biogenesis disorder 5A (Zellweger) Uncertain:1

Jul 24, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

Apr 13, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Zellweger spectrum disorders Benign:1

Nov 11, 2019

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PEX2-related disorder Benign:1

Jul 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.29	T
Eigen	Benign	0.073
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.3	L
PhyloP100		7.6
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.35
Sift	Benign	0.69	T
Sift4G	Benign	0.13	T
Polyphen		0.059	B
Vest4		0.24
MVP		0.85
ClinPred		0.070	T
GERP RS		5.7
Varity_R		0.40
gMVP		0.38
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs149287302; hg19: chr8-77896324;