chr8-76983970-T-C

Position:

• chr8-76983970-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2 BP4_Strong BP6 BS1

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

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 -7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.013303548).
• BP6: Variant 8-76983970-T-C is Benign according to our data. Variant chr8-76983970-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 282347.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=7, Benign=1}.
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PEX2	NM_000318.3	c.209A>G	p.Tyr70Cys	missense_variant	4/4	ENST00000357039.9	NP_000309.2
PEX2	NM_001079867.2	c.209A>G	p.Tyr70Cys	missense_variant	3/3		NP_001073336.2
PEX2	NM_001172086.2	c.209A>G	p.Tyr70Cys	missense_variant	5/5		NP_001165557.2
PEX2	NM_001172087.2	c.209A>G	p.Tyr70Cys	missense_variant	3/3		NP_001165558.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PEX2	ENST00000357039.9	c.209A>G	p.Tyr70Cys	missense_variant	4/4	1	NM_000318.3	ENSP00000349543.4
PEX2	ENST00000522527.5	c.209A>G	p.Tyr70Cys	missense_variant	3/3	1		ENSP00000428638.1
PEX2	ENST00000520103.5	c.209A>G	p.Tyr70Cys	missense_variant	3/3	2		ENSP00000428590.1
PEX2	ENST00000518986.5	c.209A>G	p.Tyr70Cys	missense_variant	3/3	3		ENSP00000429304.1

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

GnomAD3 exomes AF: 0.000597 AC: 150 AN: 251352 Hom.: 0 AF XY: 0.000420 AC XY: 57 AN XY: 135854

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 SAS 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

Gnomad4 AFR exome AF: 0.00842

Gnomad4 AMR exome AF: 0.000313

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: 0.00000270

Gnomad4 OTH exome AF: 0.000414

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

Gnomad4 AFR AF: 0.00790

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000284 Hom.: 0

Bravo AF: 0.00241

ESP6500AA AF: 0.00658 AC: 29

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000708 AC: 86

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 27, 2022	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jul 19, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2022	- -

Peroxisome biogenesis disorder 5A (Zellweger) Uncertain:3 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 03, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

Peroxisome biogenesis disorder 5B Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 31, 2015

- -

Computational scores

Source: dbNSFP v4.3

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;D;D;T
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	.;.;D;D
M_CAP	Benign	0.077	D
MetaRNN	Benign	0.013	T;T;T;T
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.5	M;M;M;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Benign	0.083	T;T;T;.
Polyphen		1.0	D;D;D;.
Vest4		0.39
MVP		0.92
ClinPred		0.085	T
GERP RS		4.6
Varity_R		0.76
gMVP		0.58

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: rs35689779; hg19: chr8-77896206;