6-42965788-C-T

Variant names:

• chr6-42965788-C-T
• rs2274515
• ENST00000244546.4:c.2117G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000244546.4(PEX6):​c.2117G>A​(p.Cys706Tyr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0621 in 1,612,834 control chromosomes in the GnomAD database, including 4,649 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (564 hom., cov: 32)
  • Exomes 𝑓: 0.062 (4085 hom.)
• Consequence: PEX6 ENST00000244546.4 missense, splice_region
• Scores: Splicing: ADA: 0.002506
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.32
• Publications: 16 publications found

Genes affected

PEX6 (HGNC:8859): (peroxisomal biogenesis factor 6) This gene encodes a member of the AAA (ATPases associated with diverse cellular activities) family of ATPases. This member is a predominantly cytoplasmic protein, which plays a direct role in peroxisomal protein import and is required for PTS1 (peroxisomal targeting signal 1, a C-terminal tripeptide of the sequence ser-lys-leu) receptor activity. Mutations in this gene cause peroxisome biogenesis disorders of complementation group 4 and complementation group 6. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

PEX6 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 4A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Myriad Women’s Health
• peroxisome biogenesis disorder 4B

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Heimler syndrome 2

  Inheritance: AR Classification: MODERATE Submitted by: G2P
• autosomal recessive cerebellar ataxia-blindness-deafness syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• 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=0.0014739037).
• BP6: Variant 6-42965788-C-T is Benign according to our data. Variant chr6-42965788-C-T is described in ClinVar as Benign. ClinVar VariationId is 92785.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PEX6	NM_000287.4	c.2364G>A	p.Val788Val	splice_region_variant, synonymous_variant	Exon 13 of 17	ENST00000304611.13	NP_000278.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEX6	ENST00000244546.4	c.2117G>A	p.Cys706Tyr	missense_variant, splice_region_variant	Exon 11 of 15	1		ENSP00000244546.4
PEX6	ENST00000304611.13	c.2364G>A	p.Val788Val	splice_region_variant, synonymous_variant	Exon 13 of 17	1	NM_000287.4	ENSP00000303511.8

Frequencies

GnomAD3 genomes AF: 0.0660 AC: 10041 AN: 152066 Hom.: 559 Cov.: 32

Gnomad AFR AF: 0.0532

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.151

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.150

Gnomad FIN AF: 0.0579

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0684

GnomAD2 exomes AF: 0.0901 AC: 22604 AN: 250900 AF XY: 0.0865

Gnomad AFR exome AF: 0.0548

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.0450

Gnomad EAS exome AF: 0.149

Gnomad FIN exome AF: 0.0596

Gnomad NFE exome AF: 0.0464

Gnomad OTH exome AF: 0.0789

GnomAD4 exome AF: 0.0617 AC: 90120 AN: 1460650 Hom.: 4085 Cov.: 33 AF XY: 0.0629 AC XY: 45724 AN XY: 726690

African (AFR) AF: 0.0552 AC: 1848 AN: 33452

American (AMR) AF: 0.205 AC: 9165 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.0494 AC: 1290 AN: 26126

East Asian (EAS) AF: 0.154 AC: 6121 AN: 39678

South Asian (SAS) AF: 0.130 AC: 11177 AN: 86198

European-Finnish (FIN) AF: 0.0584 AC: 3118 AN: 53352

Middle Eastern (MID) AF: 0.0506 AC: 292 AN: 5768

European-Non Finnish (NFE) AF: 0.0476 AC: 52868 AN: 1111010

Other (OTH) AF: 0.0703 AC: 4241 AN: 60348

GnomAD4 genome AF: 0.0661 AC: 10052 AN: 152184 Hom.: 564 Cov.: 32 AF XY: 0.0696 AC XY: 5178 AN XY: 74406

African (AFR) AF: 0.0530 AC: 2202 AN: 41534

American (AMR) AF: 0.151 AC: 2308 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 158 AN: 3472

East Asian (EAS) AF: 0.152 AC: 784 AN: 5158

South Asian (SAS) AF: 0.149 AC: 718 AN: 4812

European-Finnish (FIN) AF: 0.0579 AC: 613 AN: 10596

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0452 AC: 3073 AN: 68010

Other (OTH) AF: 0.0743 AC: 157 AN: 2114

Alfa AF: 0.0556 Hom.: 1445

Bravo AF: 0.0722

TwinsUK AF: 0.0458 AC: 170

ALSPAC AF: 0.0524 AC: 202

ESP6500AA AF: 0.0567 AC: 250

ESP6500EA AF: 0.0447 AC: 384

ExAC AF: 0.0860 AC: 10436

Asia WGS AF: 0.184 AC: 638 AN: 3478

EpiCase AF: 0.0447

EpiControl AF: 0.0444

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Apr 06, 2018

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: Variant c.2364G>A (p.Val788Val) affects a non-conserved neucleotide resulting a synonymous change in the ATPase, AAA-type, core domain of the encoded protein. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.086 in 276948 control chromosomes in the gnomAD database, including 1712 homozygotes. The observed variant frequency is approximately 44.65 fold of the estimated maximal expected allele frequency for a pathogenic variant in PEX6 causing Zellweger Syndrome phenotype (0.0019), strongly suggesting that the variant is benign. c.2364G>A has been reported in the literature in individuals affected with Zellweger Syndrome and authors listed variant as SNP and neutral (Yik_2009). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Multiple clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar and classified the variant as benign (2 labs)/likely benign (1 lab). Based on the evidence outlined above, the variant was classified as benign. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 30, 2013

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 4A (Zellweger) Benign:2

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 12, 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. -

not provided Benign:2

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Zellweger spectrum disorders Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Heimler syndrome 2 Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Peroxisome biogenesis disorder 4B Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Pathogenic	0.21
CADD	Benign	13
DANN	Uncertain	0.98
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.0015	T
MetaSVM	Uncertain	0.42	D
PhyloP100		1.3
PROVEAN	Benign	0.30	N
REVEL	Benign	0.29
Sift	Benign	0.11	T
Sift4G	Benign	0.16	T
Vest4		0.13
ClinPred		0.0080	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=53/47	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0025
dbscSNV1_RF	Benign	0.094
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: rs2274515; hg19: chr6-42933526; COSMIC: COSV55102634; COSMIC: COSV55102634;