8-76983431-A-C

Position:

• chr8-76983431-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000318.3(PEX2):​c.748T>G​(p.Trp250Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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. W250R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PEX2 NM_000318.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.73

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX2	NM_000318.3	c.748T>G	p.Trp250Gly	missense_variant	4/4	ENST00000357039.9	NP_000309.2
PEX2	NM_001079867.2	c.748T>G	p.Trp250Gly	missense_variant	3/3		NP_001073336.2
PEX2	NM_001172086.2	c.748T>G	p.Trp250Gly	missense_variant	5/5		NP_001165557.2
PEX2	NM_001172087.2	c.748T>G	p.Trp250Gly	missense_variant	3/3		NP_001165558.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX2	ENST00000357039.9	c.748T>G	p.Trp250Gly	missense_variant	4/4	1	NM_000318.3	ENSP00000349543	P1
PEX2	ENST00000522527.5	c.748T>G	p.Trp250Gly	missense_variant	3/3	1		ENSP00000428638	P1
PEX2	ENST00000520103.5	c.748T>G	p.Trp250Gly	missense_variant	3/3	2		ENSP00000428590	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

May 02, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	28
DANN	Benign	0.96
DEOGEN2	Uncertain	0.69	D;D;D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	.;.;T
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.89	D;D;D
MetaSVM	Uncertain	0.33	D
MutationAssessor	Uncertain	2.6	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.2	D;D;D
REVEL	Pathogenic	0.72
Sift	Benign	0.47	T;T;T
Sift4G	Benign	0.62	T;T;T
Polyphen		0.98	D;D;D
Vest4		0.83
MutPred		0.70		Loss of catalytic residue at M253 (P = 0.0094);Loss of catalytic residue at M253 (P = 0.0094);Loss of catalytic residue at M253 (P = 0.0094);
MVP		0.95
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.47
gMVP		0.69

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: rs142645936; hg19: chr8-77895667;