WDR81

protein-coding

WD repeat domain 81, the group of WD repeat domain containing|BEACH domain containing |Protein phosphatase 1 regulatory subunits|Armadillo like helical domain containing

Gene summary

This gene encodes a multi-domain transmembrane protein which is predominantly expressed in the brain and is thought to play a role in endolysosomal trafficking. Mutations in this gene are associated with an autosomal recessive form of a syndrome exhibiting cerebellar ataxia, cognitive disability, and disequilibrium (CAMRQ2). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2017]

MANE transcript

NM_001163809.2

Inheritance

ClinVar variants

P:43U:426B:205

Top phenotype

Cerebellar ataxia, impaired intellectual development, and dysquilibrium syndrome 2; Hydrocephalus, nonsyndromic, autosomal recessive 3

gnomAD constraint

pLI —, LoF o/e 0.38

Max pathogenic AF

—

Genomic locus

chr17:1,716,523-1,738,599

External References & Databases

Ensembl (ENSG00000167716)

Transcript & Mutation Effects

hg38 • Region Span ~22.1 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cerebellar ataxia, intellectual disability, and dysequilibriumSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009133

Submitter: Orphanet

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012430

Submitter: Labcorp Genetics (formerly Invitae)

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012430

Submitter: PanelApp Australia

cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0012430

Submitter: G2P

hydrocephalus, congenital, 3, with brain anomaliesSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0054794

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Cerebellar ataxia, impaired intellectual development, and dysquilibrium syndrome 2; Hydrocephalus, nonsyndromic, autosomal recessive 3AR

Manifestation: Neurologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Refs: 16371500; 21885617; 25558065; 26437881; 28556411

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WDR81 variants in ClinVar

18 Conditions Cataloged

Inborn genetic diseasesTotal: 347

not providedTotal: 294

not specifiedTotal: 92

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 2Total: 63

WDR81-related disorderTotal: 62

Hydrocephalus, congenital, 3, with brain anomaliesTotal: 27

Intellectual disabilityTotal: 3

Epileptic encephalopathyTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001163809.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			6 clinvar	157 clinvar	11 clinvar	174
missense		4 clinvar	416 clinvar	37 clinvar		457
nonsense	5 clinvar	14 clinvar	1 clinvar			20
start loss						0
frameshift	3 clinvar	14 clinvar	1 clinvar			18
splice donor/acceptor (+/-2bp)		3 clinvar	2 clinvar			5
Total	8	35	426	194	11	674

Highest pathogenic variant AF is 0.0000305986

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 25 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001163809.2	RefSeq	NP_001157281.1	10	MANE Select
ENST00000409644.6	Ensembl	ENSP00000386609.1	10	MANE Select
NM_001163673.2	RefSeq	NP_001157145.1	10	Standard
NM_001163811.2	RefSeq	NP_001157283.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

ubiquitin-dependent protein catabolic process
mitochondrion organization
negative regulation of phosphatase activity
aggrephagy
regulation of phosphatidylinositol 3-kinase activity

Molecular Function

protein binding
phosphatidylinositol 3-kinase regulator activity
K63-linked polyubiquitin modification-dependent protein binding

Cellular Component

autophagosome membrane
mitochondrion
lysosomal membrane
endoplasmic reticulum membrane
Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000409644
Coding exons: 10
Length: 22077
Individuals with no LoFs: 125557
Homozygous LoFs: 0
Heterozygous LoFs: 47
Defined: 125604
p: 0.000187

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.11	1000	1.21e+3	0.829	0.0000799	12394
Missense (PolyPhen)		391	528.73	0.7395		5658
Synonymous	1.60	502	550	0.913	0.0000389	4227
Loss of Function	4.57	24	63.2	0.380	0.00000336	664

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00063	0.00062	rare
Latino/Admixed American	0.000093	0.000087	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00016	0.00016	rare
Finnish	0.00050	0.00046	rare
European (Non-Finnish)	0.00016	0.00016	rare
South Asian	0.000066	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions as a negative regulator of the PI3 kinase/PI3K activity associated with endosomal membranes via BECN1, a core subunit of the PI3K complex. By modifying the phosphatidylinositol 3-phosphate/PtdInsP3 content of endosomal membranes may regulate endosome fusion, recycling, sorting and early to late endosome transport (PubMed:26783301). It is for instance, required for the delivery of cargos like BST2/tetherin from early to late endosome and thereby participates indirectly to their degradation by the lysosome (PubMed:27126989). May also play a role in aggrephagy, the macroautophagic degradation of ubiquitinated protein aggregates. In this process, may regulate the interaction of SQSTM1 with ubiquitinated proteins and also recruit MAP1LC3C (PubMed:28404643). May also be involved in maintenance of normal mitochondrial structure and organization (By similarity). {ECO:0000250|UniProtKB:Q5ND34, ECO:0000269|PubMed:26783301, ECO:0000269|PubMed:27126989, ECO:0000269|PubMed:28404643}.;

Intolerance Scores

LoFtool: 0.504
RVIS EVS: -1.76
RVIS percentile EVS: 2.34

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.985

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	High	Medium	High