8-76983824-G-T

Variant names:

• chr8-76983824-G-T
• rs61752123
• NM_000318.3:c.355C>A

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_000318.3(PEX2):​c.355C>A​(p.Arg119Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R119R) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: PEX2 NM_000318.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.32
• Publications: 12 publications found

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]

PEX2 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 5A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health, G2P
• peroxisome biogenesis disorder 5B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP7: Synonymous conserved (PhyloP=2.32 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000318.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX2	NM_000318.3	MANE Select	c.355C>A	p.Arg119Arg	synonymous	Exon 4 of 4	NP_000309.2
	PEX2	NM_001079867.2		c.355C>A	p.Arg119Arg	synonymous	Exon 3 of 3	NP_001073336.2
	PEX2	NM_001172086.2		c.355C>A	p.Arg119Arg	synonymous	Exon 5 of 5	NP_001165557.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX2	ENST00000357039.9	TSL:1 MANE Select	c.355C>A	p.Arg119Arg	synonymous	Exon 4 of 4	ENSP00000349543.4
	PEX2	ENST00000522527.5	TSL:1	c.355C>A	p.Arg119Arg	synonymous	Exon 3 of 3	ENSP00000428638.1
	PEX2	ENST00000520103.5	TSL:2	c.355C>A	p.Arg119Arg	synonymous	Exon 3 of 3	ENSP00000428590.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152072 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152072 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74276

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.0000655 AC: 1 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2084

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.6
DANN	Benign	0.56
PhyloP100		2.3

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

Other links and lift over

dbSNP: rs61752123; hg19: chr8-77896060;