8-76984088-G-T

Position:

• chr8-76984088-G-T

Variant summary

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

The NM_000318.3(PEX2):​c.91C>A​(p.Gln31Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,260 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q31E) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PEX2 NM_000318.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.64

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	Protein	UniProt
PEX2	NM_000318.3	c.91C>A	p.Gln31Lys	missense_variant	4/4	ENST00000357039.9	NP_000309.2
PEX2	NM_001079867.2	c.91C>A	p.Gln31Lys	missense_variant	3/3		NP_001073336.2
PEX2	NM_001172086.2	c.91C>A	p.Gln31Lys	missense_variant	5/5		NP_001165557.2
PEX2	NM_001172087.2	c.91C>A	p.Gln31Lys	missense_variant	3/3		NP_001165558.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX2	ENST00000357039.9	c.91C>A	p.Gln31Lys	missense_variant	4/4	1	NM_000318.3	ENSP00000349543.4
PEX2	ENST00000522527.5	c.91C>A	p.Gln31Lys	missense_variant	3/3	1		ENSP00000428638.1
PEX2	ENST00000520103.5	c.91C>A	p.Gln31Lys	missense_variant	3/3	2		ENSP00000428590.1
PEX2	ENST00000518986.5	c.91C>A	p.Gln31Lys	missense_variant	3/3	3		ENSP00000429304.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000799 AC: 2 AN: 250288 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135272

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000329

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460260 Hom.: 0 Cov.: 35 AF XY: 0.00000275 AC XY: 2 AN XY: 726314

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: 0.0000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T;T;T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	.;.;D;D
M_CAP	Benign	0.068	D
MetaRNN	Uncertain	0.52	D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.3	M;M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.70	N;N;N;N
REVEL	Uncertain	0.43
Sift	Benign	0.12	T;T;T;T
Sift4G	Benign	0.54	T;T;T;.
Polyphen		0.81	P;P;P;.
Vest4		0.49
MutPred		0.59		Gain of methylation at Q31 (P = 0.031);Gain of methylation at Q31 (P = 0.031);Gain of methylation at Q31 (P = 0.031);Gain of methylation at Q31 (P = 0.031);
MVP		0.89
ClinPred		0.60	D
GERP RS		5.7
Varity_R		0.54
gMVP		0.50

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: rs149287302; hg19: chr8-77896324;