2-61048636-C-G

Variant names:

• chr2-61048636-C-G
• rs74350038
• NM_002618.4:c.1078C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002618.4(PEX13):​c.1078C>G​(p.Leu360Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0337 in 1,614,022 control chromosomes in the GnomAD database, including 1,104 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L360L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.024 (72 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1032 hom.)
• Consequence: PEX13 NM_002618.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.626
• Publications: 17 publications found

Genes affected

PEX13 (HGNC:8855): (peroxisomal biogenesis factor 13) This gene encodes a peroxisomal membrane protein that binds the type 1 peroxisomal targeting signal receptor via a SH3 domain located in the cytoplasm. Mutations and deficiencies in peroxisomal protein importing and peroxisome assembly lead to peroxisomal biogenesis disorders, an example of which is Zellweger syndrome. [provided by RefSeq, Oct 2008]

PEX13 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 11A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• peroxisome biogenesis disorder 11B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025173426).
• BP6: Variant 2-61048636-C-G is Benign according to our data. Variant chr2-61048636-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 336670.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0238 (3630/152278) while in subpopulation NFE AF = 0.0386 (2627/68022). AF 95% confidence interval is 0.0374. There are 72 homozygotes in GnomAd4. There are 1716 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 72 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX13	NM_002618.4	c.1078C>G	p.Leu360Val	missense_variant	Exon 4 of 4	ENST00000295030.6	NP_002609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX13	ENST00000295030.6	c.1078C>G	p.Leu360Val	missense_variant	Exon 4 of 4	1	NM_002618.4	ENSP00000295030.4

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3627 AN: 152160 Hom.: 72 Cov.: 33

Gnomad AFR AF: 0.00736

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0181

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00766

Gnomad FIN AF: 0.0266

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0386

Gnomad OTH AF: 0.0282

GnomAD2 exomes AF: 0.0239 AC: 5998 AN: 251474 AF XY: 0.0239

Gnomad AFR exome AF: 0.00658

Gnomad AMR exome AF: 0.0129

Gnomad ASJ exome AF: 0.00794

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.0276

Gnomad NFE exome AF: 0.0382

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0347 AC: 50785 AN: 1461744 Hom.: 1032 Cov.: 31 AF XY: 0.0341 AC XY: 24797 AN XY: 727168

African (AFR) AF: 0.00520 AC: 174 AN: 33480

American (AMR) AF: 0.0132 AC: 590 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00819 AC: 214 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.00926 AC: 799 AN: 86258

European-Finnish (FIN) AF: 0.0300 AC: 1602 AN: 53420

Middle Eastern (MID) AF: 0.0222 AC: 128 AN: 5768

European-Non Finnish (NFE) AF: 0.0409 AC: 45485 AN: 1111878

Other (OTH) AF: 0.0297 AC: 1792 AN: 60394

GnomAD4 genome AF: 0.0238 AC: 3630 AN: 152278 Hom.: 72 Cov.: 33 AF XY: 0.0230 AC XY: 1716 AN XY: 74454

African (AFR) AF: 0.00734 AC: 305 AN: 41560

American (AMR) AF: 0.0181 AC: 276 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00779 AC: 27 AN: 3468

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

South Asian (SAS) AF: 0.00849 AC: 41 AN: 4828

European-Finnish (FIN) AF: 0.0266 AC: 282 AN: 10604

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0386 AC: 2627 AN: 68022

Other (OTH) AF: 0.0279 AC: 59 AN: 2112

Alfa AF: 0.0340 Hom.: 78

Bravo AF: 0.0225

TwinsUK AF: 0.0429 AC: 159

ALSPAC AF: 0.0462 AC: 178

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0379 AC: 326

ExAC AF: 0.0241 AC: 2922

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.0344

EpiControl AF: 0.0371

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 27, 2023

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Peroxisome biogenesis disorder 11A (Zellweger) Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	5.3
DANN	Benign	0.049
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.048	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N
PhyloP100		-0.63
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.21	N
REVEL	Benign	0.15
Sift	Benign	0.47	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.030
MPC		0.085
ClinPred		0.000071	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.025
gMVP		0.19
Mutation Taster		=97/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs74350038; hg19: chr2-61275771; COSMIC: COSV54371007;