rs61752119

Positions:

• chr8-76984016-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000318.3(PEX2):​c.163G>A​(p.Glu55Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,461,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: PEX2 NM_000318.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.57

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant 8-76984016-C-T is Pathogenic according to our data. Variant chr8-76984016-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13705.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX2	NM_000318.3	c.163G>A	p.Glu55Lys	missense_variant	4/4	ENST00000357039.9	NP_000309.2
PEX2	NM_001079867.2	c.163G>A	p.Glu55Lys	missense_variant	3/3		NP_001073336.2
PEX2	NM_001172086.2	c.163G>A	p.Glu55Lys	missense_variant	5/5		NP_001165557.2
PEX2	NM_001172087.2	c.163G>A	p.Glu55Lys	missense_variant	3/3		NP_001165558.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX2	ENST00000357039.9	c.163G>A	p.Glu55Lys	missense_variant	4/4	1	NM_000318.3	ENSP00000349543.4
PEX2	ENST00000522527.5	c.163G>A	p.Glu55Lys	missense_variant	3/3	1		ENSP00000428638.1
PEX2	ENST00000520103.5	c.163G>A	p.Glu55Lys	missense_variant	3/3	2		ENSP00000428590.1
PEX2	ENST00000518986.5	c.163G>A	p.Glu55Lys	missense_variant	3/3	3		ENSP00000429304.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1461570 Hom.: 0 Cov.: 35 AF XY: 0.0000151 AC XY: 11 AN XY: 727046

Gnomad4 AFR exome AF: 0.0000299

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: 0.0000252

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 27, 2023

Variant summary: PEX2 c.163G>A (p.Glu55Lys) results in a conservative amino acid change to a highly conserved residue (HGMD) located in the Pex, N-terminal (IPR006845) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251214 control chromosomes (gnomAD). c.163G>A has been reported in the literature in an individual affected with Refsum disease who was compound heterozygous with a pathogenic variant (Imamura_1998, Shimozawa_1999). These data suggest the variant may be associated with disease. At least two publications report experimental evidence evaluating an impact on protein function, finding that cells expressing the variant protein showed partially reduced enzymatic activity and recapitulated the catalase-less persoxisomes seen in patient cells (Fujiwara_2000, Shimozawa_1999). The following publications have been ascertained in the context of this evaluation (PMID: 9585609, 10528859, 10960480). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Peroxisome biogenesis disorder 5B Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Pathogenic	0.49	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.89	D;D;D;D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	.;.;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.98	D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	3.2	M;M;M;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Pathogenic	0.90
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.
Polyphen		1.0	D;D;D;.
Vest4		0.90
MutPred		0.96		Gain of MoRF binding (P = 0.0092);Gain of MoRF binding (P = 0.0092);Gain of MoRF binding (P = 0.0092);Gain of MoRF binding (P = 0.0092);
MVP		0.94
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.23		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61752119; hg19: chr8-77896252;