8-76983446-C-T

Position:

chr8-76983446-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

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

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 -20 ACMG points.

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 id 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/exons	MANE	Protein	UniProt
PEX2	NM_000318.3 linkuse as main transcript	c.733G>A	p.Ala245Thr	missense_variant	4/4	ENST00000357039.9	NP_000309.2	P28328
PEX2	NM_001079867.2 linkuse as main transcript	c.733G>A	p.Ala245Thr	missense_variant	3/3		NP_001073336.2	P28328
PEX2	NM_001172086.2 linkuse as main transcript	c.733G>A	p.Ala245Thr	missense_variant	5/5		NP_001165557.2	P28328
PEX2	NM_001172087.2 linkuse as main transcript	c.733G>A	p.Ala245Thr	missense_variant	3/3		NP_001165558.2	P28328

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
PEX2	ENST00000357039.9 linkuse as main transcript	c.733G>A	p.Ala245Thr	missense_variant	4/4	1	NM_000318.3	ENSP00000349543.4	P28328
PEX2	ENST00000522527.5 linkuse as main transcript	c.733G>A	p.Ala245Thr	missense_variant	3/3	1		ENSP00000428638.1	P28328
PEX2	ENST00000520103.5 linkuse as main transcript	c.733G>A	p.Ala245Thr	missense_variant	3/3	2		ENSP00000428590.1	P28328

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

GnomAD3 exomes

AF:

0.00684

AC:

1719

AN:

251258

Hom.:

AF XY:

0.00511

AC XY:

694

AN XY:

135814

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 SAS exome

AF:

0.000327

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

Gnomad4 AFR exome

AF:

0.0964

Gnomad4 AMR exome

AF:

0.00483

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000243

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000129

Gnomad4 OTH exome

AF:

0.00601

GnomAD4 genome

AF:

0.0267

AC:

4064

AN:

152238

Hom.:

189

Cov.:

AF XY:

0.0255

AC XY:

1902

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0923

Gnomad4 AMR

AF:

0.0105

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000622

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.0203

Alfa

AF:

0.00275

Hom.:

Bravo

AF:

0.0296

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Peroxisome biogenesis disorder 5A (Zellweger)

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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 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

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Zellweger spectrum disorders

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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

DANN

Benign

0.93

DEOGEN2

Benign

0.38

T;T;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.37

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.67

.;.;T

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

1.1

L;L;L

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.21

Sift

Benign

0.16

T;T;T

Sift4G

Uncertain

0.038

D;D;D

Polyphen

0.57

P;P;P

Vest4

0.11

MVP

0.82

ClinPred

0.013

GERP RS

2.8

Varity_R

0.053

gMVP

0.44

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