8-76983446-C-T

Variant names:

• chr8-76983446-C-T
• rs112108739
• NM_000318.3:c.733G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000318.3(PEX2):​c.733G>A​(p.Ala245Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.005 in 1,614,058 control chromosomes in the GnomAD database, including 372 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A245P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.027 (189 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (183 hom.)
• Consequence: PEX2 NM_000318.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.38
• Publications: 6 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: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_000318.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0045028925).
• BP6: Variant 8-76983446-C-T is Benign according to our data. Variant chr8-76983446-C-T is described in ClinVar as Benign. ClinVar VariationId is 255818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

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.733G>A	p.Ala245Thr	missense	Exon 4 of 4	NP_000309.2	P28328
	PEX2	NM_001079867.2		c.733G>A	p.Ala245Thr	missense	Exon 3 of 3	NP_001073336.2	P28328
	PEX2	NM_001172086.2		c.733G>A	p.Ala245Thr	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.733G>A	p.Ala245Thr	missense	Exon 4 of 4	ENSP00000349543.4	P28328
	PEX2	ENST00000522527.5	TSL:1	c.733G>A	p.Ala245Thr	missense	Exon 3 of 3	ENSP00000428638.1	P28328
	PEX2	ENST00000520103.5	TSL:2	c.733G>A	p.Ala245Thr	missense	Exon 3 of 3	ENSP00000428590.1	P28328

Frequencies

GnomAD3 genomes AF: 0.0266 AC: 4045 AN: 152118 Hom.: 186 Cov.: 32

Gnomad AFR AF: 0.0921

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0105

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.00684 AC: 1719 AN: 251258 AF XY: 0.00511

Gnomad AFR exome AF: 0.0927

Gnomad AMR exome AF: 0.00413

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000246

Gnomad OTH exome AF: 0.00457

GnomAD4 exome AF: 0.00274 AC: 4000 AN: 1461820 Hom.: 183 Cov.: 32 AF XY: 0.00238 AC XY: 1733 AN XY: 727222

African (AFR) AF: 0.0964 AC: 3227 AN: 33478

American (AMR) AF: 0.00483 AC: 216 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26136

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

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53366

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.000129 AC: 144 AN: 1112004

Other (OTH) AF: 0.00601 AC: 363 AN: 60394

GnomAD4 genome AF: 0.0267 AC: 4064 AN: 152238 Hom.: 189 Cov.: 32 AF XY: 0.0255 AC XY: 1902 AN XY: 74444

African (AFR) AF: 0.0923 AC: 3831 AN: 41518

American (AMR) AF: 0.0105 AC: 161 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000309 AC: 21 AN: 68024

Other (OTH) AF: 0.0203 AC: 43 AN: 2114

Alfa AF: 0.00859 Hom.: 87

Bravo AF: 0.0296

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0906 AC: 399

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00847 AC: 1028

Asia WGS AF: 0.00549 AC: 19 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Peroxisome biogenesis disorder 5A (Zellweger) (2)
-	-	1	not specified (1)
-	-	1	Zellweger spectrum disorders (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	11
DANN	Benign	0.93
DEOGEN2	Benign	0.38	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.37
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.4
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.21
Sift	Benign	0.16	T
Sift4G	Uncertain	0.038	D
Polyphen		0.57	P
Vest4		0.11
MVP		0.82
ClinPred		0.013	T
GERP RS		2.8
Varity_R		0.053
gMVP		0.44
Mutation Taster		=95/5	polymorphism (auto)

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: rs112108739; hg19: chr8-77895682;