chr22-18078297-C-T

Variant names:

• chr22-18078297-C-T
• rs1926378615
• ENST00000329627.11:c.-80C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_017929.6(PEX26):​c.-80C>T variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PEX26 NM_017929.6 splice_region
• Scores: Splicing: ADA: 0.0001774
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.744
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017929.6. 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.-80C>T		5_prime_UTR	Exon 1 of 5	NP_001121121.1	Q7Z412-1
	PEX26	NM_017929.6		c.-80C>T		splice_region	Exon 2 of 6	NP_060399.1	Q7Z412-1
	PEX26	NM_001199319.2		c.-80C>T		splice_region	Exon 2 of 5	NP_001186248.1	Q7Z412-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEX26	ENST00000329627.11	TSL:1	c.-80C>T		splice_region	Exon 2 of 6	ENSP00000331106.5	Q7Z412-1
	PEX26	ENST00000399744.8	TSL:1 MANE Select	c.-80C>T		5_prime_UTR	Exon 1 of 5	ENSP00000382648.4	Q7Z412-1
	PEX26	ENST00000329627.11	TSL:1	c.-80C>T		5_prime_UTR	Exon 2 of 6	ENSP00000331106.5	Q7Z412-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 879352 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 453782

African (AFR) AF: 0.00 AC: 0 AN: 22222

American (AMR) AF: 0.00 AC: 0 AN: 35904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21990

East Asian (EAS) AF: 0.00 AC: 0 AN: 34126

South Asian (SAS) AF: 0.00 AC: 0 AN: 69218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4692

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 611414

Other (OTH) AF: 0.00 AC: 0 AN: 41116

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Peroxisome biogenesis disorder 7A (Zellweger) (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	4.2
DANN	Benign	0.84
PhyloP100		-0.74
PromoterAI		-0.075	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.010
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: rs1926378615; hg19: chr22-18561063;