8-76983806-G-C

Position:

• chr8-76983806-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000318.3(PEX2):​c.373C>G​(p.Arg125Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R125Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PEX2 NM_000318.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX2	NM_000318.3	c.373C>G	p.Arg125Gly	missense_variant	4/4	ENST00000357039.9
PEX2	NM_001079867.2	c.373C>G	p.Arg125Gly	missense_variant	3/3
PEX2	NM_001172086.2	c.373C>G	p.Arg125Gly	missense_variant	5/5
PEX2	NM_001172087.2	c.373C>G	p.Arg125Gly	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX2	ENST00000357039.9	c.373C>G	p.Arg125Gly	missense_variant	4/4	1	NM_000318.3	P1
PEX2	ENST00000522527.5	c.373C>G	p.Arg125Gly	missense_variant	3/3	1		P1
PEX2	ENST00000520103.5	c.373C>G	p.Arg125Gly	missense_variant	3/3	2		P1
PEX2	ENST00000518986.5	c.373C>G	p.Arg125Gly	missense_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461828 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 727202

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 5A (Zellweger) Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 25, 2022

This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 125 of the PEX2 protein (p.Arg125Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PEX2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T;T;T;T
Eigen	Benign	-0.026
Eigen_PC	Benign	0.097
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.087	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.9	L;L;L;.
MutationTaster	Benign	0.50	D;D;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.78	N;N;N;N
REVEL	Uncertain	0.54
Sift	Benign	0.23	T;T;T;T
Sift4G	Benign	0.52	T;T;T;.
Polyphen		0.19	B;B;B;.
Vest4		0.46
MutPred		0.54		Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);Loss of sheet (P = 0.0142);
MVP		0.88
ClinPred		0.66	D
GERP RS		4.3
Varity_R		0.12
gMVP		0.36

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: rs61752124; hg19: chr8-77896042;