8-76980884-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000318.3(PEX2):c.*2377A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.952 in 152,294 control chromosomes in the GnomAD database, including 69,148 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.95 (69146 hom., cov: 32)
  • Exomes 𝑓: 1.0 (2 hom.)
• Consequence: PEX2 NM_000318.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.600

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 8-76980884-T-C is Benign according to our data. Variant chr8-76980884-T-C is described in ClinVar as [Benign]. Clinvar id is 363777.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PEX2	NM_000318.3	c.*2377A>G		3_prime_UTR_variant	4/4	ENST00000357039.9
PEX2	NM_001079867.2	c.*2377A>G		3_prime_UTR_variant	3/3
PEX2	NM_001172086.2	c.*2377A>G		3_prime_UTR_variant	5/5
PEX2	NM_001172087.2	c.*2377A>G		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PEX2	ENST00000357039.9	c.*2377A>G		3_prime_UTR_variant	4/4	1	NM_000318.3	P1

Frequencies

GnomAD3 genomes AF: 0.952 AC: 144870 AN: 152172 Hom.: 69106 Cov.: 32

Gnomad AFR AF: 0.887

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.982

Gnomad ASJ AF: 0.993

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.964

Gnomad FIN AF: 0.941

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.980

Gnomad OTH AF: 0.962

GnomAD4 exome AF: 1.00 AC: 4 AN: 4 Hom.: 2 Cov.: 0 AF XY: 1.00 AC XY: 4 AN XY: 4

Gnomad4 NFE exome AF: 1.00

GnomAD4 genome AF: 0.952 AC: 144965 AN: 152290 Hom.: 69146 Cov.: 32 AF XY: 0.951 AC XY: 70825 AN XY: 74464

Gnomad4 AFR AF: 0.887

Gnomad4 AMR AF: 0.982

Gnomad4 ASJ AF: 0.993

Gnomad4 EAS AF: 0.991

Gnomad4 SAS AF: 0.964

Gnomad4 FIN AF: 0.941

Gnomad4 NFE AF: 0.980

Gnomad4 OTH AF: 0.962

Alfa AF: 0.971 Hom.: 25355

Bravo AF: 0.954

Asia WGS AF: 0.979 AC: 3404 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peroxisome biogenesis disorder 5A (Zellweger) Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.0
Dann	Benign	0.42

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: rs4388434; hg19: chr8-77893120;