rs35689779

Variant names:

• chr8-76983970-T-C
• rs35689779
• NM_000318.3:c.209A>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_000318.3(PEX2):​c.209A>G​(p.Tyr70Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00041 in 1,614,050 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (0 hom.)
• Consequence: PEX2 NM_000318.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9 B:2
• Conservation: PhyloP100: 3.98
• Publications: 3 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: G2P, Myriad Women’s Health
• 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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013303548).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00222 (338/152210) while in subpopulation AFR AF = 0.0079 (328/41508). AF 95% confidence interval is 0.0072. There are 1 homozygotes in GnomAd4. There are 147 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX2	NM_000318.3	MANE Select	c.209A>G	p.Tyr70Cys	missense	Exon 4 of 4	NP_000309.2	P28328
	PEX2	NM_001079867.2		c.209A>G	p.Tyr70Cys	missense	Exon 3 of 3	NP_001073336.2	P28328
	PEX2	NM_001172086.2		c.209A>G	p.Tyr70Cys	missense	Exon 5 of 5	NP_001165557.2	P28328

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX2	ENST00000357039.9	TSL:1 MANE Select	c.209A>G	p.Tyr70Cys	missense	Exon 4 of 4	ENSP00000349543.4	P28328
	PEX2	ENST00000522527.5	TSL:1	c.209A>G	p.Tyr70Cys	missense	Exon 3 of 3	ENSP00000428638.1	P28328
	PEX2	ENST00000520103.5	TSL:2	c.209A>G	p.Tyr70Cys	missense	Exon 3 of 3	ENSP00000428590.1	P28328

Frequencies

GnomAD3 genomes AF: 0.00222 AC: 338 AN: 152092 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00793

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.00143

GnomAD2 exomes AF: 0.000597 AC: 150 AN: 251352 AF XY: 0.000420

Gnomad AFR exome AF: 0.00856

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000222 AC: 324 AN: 1461840 Hom.: 0 Cov.: 35 AF XY: 0.000199 AC XY: 145 AN XY: 727226

African (AFR) AF: 0.00842 AC: 282 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111972

Other (OTH) AF: 0.000414 AC: 25 AN: 60392

GnomAD4 genome AF: 0.00222 AC: 338 AN: 152210 Hom.: 1 Cov.: 32 AF XY: 0.00197 AC XY: 147 AN XY: 74434

African (AFR) AF: 0.00790 AC: 328 AN: 41508

American (AMR) AF: 0.000458 AC: 7 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000729 Hom.: 1

Bravo AF: 0.00241

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000708 AC: 86

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	5	-	not provided (5)
-	3	1	Peroxisome biogenesis disorder 5A (Zellweger) (4)
-	-	1	not specified (1)
-	1	-	Peroxisome biogenesis disorder 5B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.097	T
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.75	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.0
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.083	T
Polyphen		1.0	D
Vest4		0.39
MVP		0.92
ClinPred		0.085	T
GERP RS		4.6
Varity_R		0.76
gMVP		0.58
Mutation Taster		=66/34	polymorphism

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: rs35689779; hg19: chr8-77896206;