8-76984088-G-C

Position:

• chr8-76984088-G-C

Variant summary

Our verdict is Benign. Variant got -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).

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 92838.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=2, Benign=2}. Variant chr8-76984088-G-C is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX2	NM_000318.3	c.91C>G	p.Gln31Glu	missense_variant	4/4	ENST00000357039.9	NP_000309.2
PEX2	NM_001079867.2	c.91C>G	p.Gln31Glu	missense_variant	3/3		NP_001073336.2
PEX2	NM_001172086.2	c.91C>G	p.Gln31Glu	missense_variant	5/5		NP_001165557.2
PEX2	NM_001172087.2	c.91C>G	p.Gln31Glu	missense_variant	3/3		NP_001165558.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX2	ENST00000357039.9	c.91C>G	p.Gln31Glu	missense_variant	4/4	1	NM_000318.3	ENSP00000349543.4
PEX2	ENST00000522527.5	c.91C>G	p.Gln31Glu	missense_variant	3/3	1		ENSP00000428638.1
PEX2	ENST00000520103.5	c.91C>G	p.Gln31Glu	missense_variant	3/3	2		ENSP00000428590.1
PEX2	ENST00000518986.5	c.91C>G	p.Gln31Glu	missense_variant	3/3	3		ENSP00000429304.1

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

GnomAD3 exomes AF: 0.00250 AC: 626 AN: 250288 Hom.: 8 AF XY: 0.00258 AC XY: 349 AN XY: 135272

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 SAS exome AF: 0.0000658

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

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.000629

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000929

Gnomad4 FIN exome AF: 0.0168

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.00128

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

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0161

Gnomad4 NFE AF: 0.00109

Gnomad4 OTH AF: 0.00237

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

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	PEX2: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, 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, 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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 24, 2017

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 13, 2017

- -

Zellweger spectrum disorders Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 11, 2019

- -

PEX2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 23, 2019

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 v4.3

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;T;T;T
Eigen	Benign	0.073
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.83	.;.;T;T
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.3	L;L;L;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.68	N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.69	T;T;T;T
Sift4G	Benign	0.13	T;T;T;.
Polyphen		0.059	B;B;B;.
Vest4		0.24
MVP		0.85
ClinPred		0.070	T
GERP RS		5.7
Varity_R		0.40
gMVP		0.38

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

Other links and lift over

dbSNP: rs149287302; hg19: chr8-77896324;