22-18083522-C-G

Variant names:

• chr22-18083522-C-G
• rs12484657
• NM_001127649.3:c.457C>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_001127649.3(PEX26):​c.457C>G​(p.Leu153Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,614,136 control chromosomes in the GnomAD database, including 232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 33)
  • Exomes 𝑓: 0.016 (211 hom.)
• Consequence: PEX26 NM_001127649.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.22
• Publications: 33 publications found

Genes affected

PEX26 (HGNC:22965): (peroxisomal biogenesis factor 26) This gene belongs to the peroxin-26 gene family. It is probably required for protein import into peroxisomes. It anchors PEX1 and PEX6 to peroxisome membranes, possibly to form heteromeric AAA ATPase complexes required for the import of proteins into peroxisomes. Defects in this gene are the cause of peroxisome biogenesis disorder complementation group 8 (PBD-CG8). PBD refers to a group of peroxisomal disorders arising from a failure of protein import into the peroxisomal membrane or matrix. The PBD group is comprised of four disorders: Zellweger syndrome (ZWS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and classical rhizomelic chondrodysplasia punctata (RCDP). Alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Dec 2010]

PEX26 Gene-Disease associations (from GenCC):

• peroxisome biogenesis disorder

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• peroxisome biogenesis disorder 7A (Zellweger)

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• peroxisome biogenesis disorder 7B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics
• Zellweger spectrum disorders

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000288683 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.009204537).
• BP6: Variant 22-18083522-C-G is Benign according to our data. Variant chr22-18083522-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 95877.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 = 0.0106 (1610/152348) while in subpopulation NFE AF = 0.0174 (1181/68030). AF 95% confidence interval is 0.0165. There are 21 homozygotes in GnomAd4. There are 726 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001127649.3. 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
	PEX26	NM_001127649.3	MANE Select	c.457C>G	p.Leu153Val	missense	Exon 3 of 5	NP_001121121.1	Q7Z412-1
	PEX26	NM_017929.6		c.457C>G	p.Leu153Val	missense	Exon 4 of 6	NP_060399.1	Q7Z412-1
	PEX26	NM_001199319.2		c.457C>G	p.Leu153Val	missense	Exon 4 of 5	NP_001186248.1	Q7Z412-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX26	ENST00000399744.8	TSL:1 MANE Select	c.457C>G	p.Leu153Val	missense	Exon 3 of 5	ENSP00000382648.4	Q7Z412-1
	PEX26	ENST00000329627.11	TSL:1	c.457C>G	p.Leu153Val	missense	Exon 4 of 6	ENSP00000331106.5	Q7Z412-1
	PEX26	ENST00000428061.2	TSL:1	c.457C>G	p.Leu153Val	missense	Exon 3 of 4	ENSP00000412441.2	Q7Z412-2

Frequencies

GnomAD3 genomes AF: 0.0106 AC: 1611 AN: 152230 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00326

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00104

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0174

Gnomad OTH AF: 0.0143

GnomAD2 exomes AF: 0.0102 AC: 2557 AN: 251270 AF XY: 0.0104

Gnomad AFR exome AF: 0.00351

Gnomad AMR exome AF: 0.00844

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00166

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.0157 AC: 22897 AN: 1461788 Hom.: 211 Cov.: 32 AF XY: 0.0153 AC XY: 11152 AN XY: 727182

African (AFR) AF: 0.00272 AC: 91 AN: 33480

American (AMR) AF: 0.00926 AC: 414 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0135 AC: 352 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000719 AC: 62 AN: 86252

European-Finnish (FIN) AF: 0.00183 AC: 98 AN: 53416

Middle Eastern (MID) AF: 0.00433 AC: 25 AN: 5768

European-Non Finnish (NFE) AF: 0.0189 AC: 21046 AN: 1111928

Other (OTH) AF: 0.0134 AC: 809 AN: 60384

GnomAD4 genome AF: 0.0106 AC: 1610 AN: 152348 Hom.: 21 Cov.: 33 AF XY: 0.00974 AC XY: 726 AN XY: 74506

African (AFR) AF: 0.00325 AC: 135 AN: 41588

American (AMR) AF: 0.0132 AC: 202 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 49 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00104 AC: 11 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0174 AC: 1181 AN: 68030

Other (OTH) AF: 0.0142 AC: 30 AN: 2116

Alfa AF: 0.0160 Hom.: 23

Bravo AF: 0.0119

TwinsUK AF: 0.0178 AC: 66

ALSPAC AF: 0.0208 AC: 80

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.0176 AC: 151

ExAC AF: 0.00996 AC: 1209

Asia WGS AF: 0.00115 AC: 5 AN: 3478

EpiCase AF: 0.0167

EpiControl AF: 0.0181

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	3	not specified (3)
-	-	1	Peroxisome biogenesis disorder 1A (Zellweger) (1)
-	-	1	Peroxisome biogenesis disorder 7A (Zellweger) (1)
-	-	1	Peroxisome biogenesis disorder 7B;C3888385:Peroxisome biogenesis disorder 7A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	0.57	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.51
Sift	Benign	0.054	T
Sift4G	Benign	0.12	T
Polyphen		1.0	D
Vest4		0.83
MPC		0.69
ClinPred		0.021	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.14
gMVP		0.23
Mutation Taster		=92/8	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: rs12484657; hg19: chr22-18566288;