8-76983446-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000318.3(PEX2):c.733G>A(p.Ala245Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,614,058 control chromosomes in the GnomAD database, including 372 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A245P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.027 ( 189 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 183 hom. )

Consequence

PEX2
NM_000318.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.38

Publications

6 publications found

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 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

PEX2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_000318.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0045028925).

BP6

Variant 8-76983446-C-T is Benign according to our data. Variant chr8-76983446-C-T is described in ClinVar as Benign. ClinVar VariationId is 255818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
PEX2	NM_000318.3 link	c.733G>A	p.Ala245Thr	missense_variant	Exon 4 of 4	ENST00000357039.9	NP_000309.2
PEX2	NM_001079867.2 link	c.733G>A	p.Ala245Thr	missense_variant	Exon 3 of 3		NP_001073336.2
PEX2	NM_001172086.2 link	c.733G>A	p.Ala245Thr	missense_variant	Exon 5 of 5		NP_001165557.2
PEX2	NM_001172087.2 link	c.733G>A	p.Ala245Thr	missense_variant	Exon 3 of 3		NP_001165558.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
PEX2	ENST00000357039.9 link	c.733G>A	p.Ala245Thr	missense_variant	Exon 4 of 4	1	NM_000318.3	ENSP00000349543.4
PEX2	ENST00000522527.5 link	c.733G>A	p.Ala245Thr	missense_variant	Exon 3 of 3	1		ENSP00000428638.1
PEX2	ENST00000520103.5 link	c.733G>A	p.Ala245Thr	missense_variant	Exon 3 of 3	2		ENSP00000428590.1
PEX2	ENST00000518986.5 link	c.*194G>A		downstream_gene_variant		3		ENSP00000429304.1

Frequencies

GnomAD3 genomes

AF:

0.0266

AC:

4045

AN:

152118

Hom.:

186

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0921

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0105

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.0206

GnomAD2 exomes

AF:

0.00684

AC:

1719

AN:

251258

AF XY:

0.00511

show subpopulations

Gnomad AFR exome

AF:

0.0927

Gnomad AMR exome

AF:

0.00413

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000246

Gnomad OTH exome

AF:

0.00457

GnomAD4 exome

AF:

0.00274

AC:

4000

AN:

1461820

Hom.:

183

Cov.:

AF XY:

0.00238

AC XY:

1733

AN XY:

727222

show subpopulations

African (AFR)

AF:

0.0964

AC:

3227

AN:

33478

American (AMR)

AF:

0.00483

AC:

216

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.000344

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.000243

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53366

Middle Eastern (MID)

AF:

0.00347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000129

AC:

144

AN:

1112004

Other (OTH)

AF:

0.00601

AC:

363

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

231

462

692

923

1154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0267

AC:

4064

AN:

152238

Hom.:

189

Cov.:

AF XY:

0.0255

AC XY:

1902

AN XY:

74444

show subpopulations

African (AFR)

AF:

0.0923

AC:

3831

AN:

41518

American (AMR)

AF:

0.0105

AC:

161

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.000622

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68024

Other (OTH)

AF:

0.0203

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

179

358

537

716

895

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00859

Hom.:

Bravo

AF:

0.0296

TwinsUK

AF:

0.000270

AC:

ESP6500AA

AF:

0.0906

AC:

399

ESP6500EA

AF:

0.000814

AC:

ExAC

AF:

0.00847

AC:

1028

Asia WGS

AF:

0.00549

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jun 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Peroxisome biogenesis disorder 5A (Zellweger)

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Zellweger spectrum disorders

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.38

T;T;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.37

LIST_S2

Benign

0.0

.;.;T

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.1

L;L;L

PhyloP100

1.4

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.3

N;N;N

Sift

Benign

0.16

T;T;T

Sift4G

Uncertain

0.038

D;D;D

Vest4

0.11

ClinPred

0.013

GERP RS

2.8

Varity_R

0.053

gMVP

0.44

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over