WDR62

protein-coding

WD repeat domain 62, the group of WD repeat domain containing

Gene summary

This gene is proposed to play a role in cerebral cortical development. Mutations in this gene have been associated with microencephaly, cortical malformations, and cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2011]

Previous symbols:

C19orf14
MCPH2

MANE transcript

NM_001083961.2

Inheritance

ClinVar variants

P:149U:471B:257

Top phenotype

Microcephaly 2, primary, autosomal recessive, with or without cortical malformations

gnomAD constraint

pLI —, LoF o/e 0.67

Max pathogenic AF

—

Genomic locus

chr19:36,054,649-36,105,108

External References & Databases

Ensembl (ENSG00000075702)

Transcript & Mutation Effects

hg38 • Region Span ~50.5 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly 2, primary, autosomal recessive, with or without cortical malformationsDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011435

Submitter: ClinGen

WDR62 was first reported in relation to autosomal recessive primary microcephaly in 2010 (Bilguvar et al., PMID: 20729831). At least 8 variants (splicing, nonsense, and frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 8 probands in 2 publications (PMIDs: 20729831, 20890278). Variants in this gene segregated with disease in 2 additional family members. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) and experimental evidence (6 pts.) has been reached. The mechanism for disease is loss of function. This gene-disease association is supported by animal models, in vitro functional assays, expression studies, and a rescue study. In summary, WDR62 is definitively associated with autosomal recessive primary microcephaly. This classification was approved by the ClinGen Brain Malformations GCEP on May 26, 2020 (SOP Version 7).

microcephaly 2, primary, autosomal recessive, with or without cortical malformationsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011435

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

microcephaly 2, primary, autosomal recessive, with or without cortical malformationsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011435

Submitter: PanelApp Australia

microcephaly 2, primary, autosomal recessive, with or without cortical malformationsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011435

Submitter: Labcorp Genetics (formerly Invitae)

microcephaly 2, primary, autosomal recessive, with or without cortical malformationsSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011435

Submitter: Ambry Genetics

autosomal recessive primary microcephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: Orphanet

microcephaly 2, primary, autosomal recessive, with or without cortical malformationsDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011435

Submitter: Illumina

microcephaly 2, primary, autosomal recessive, with or without cortical malformationsDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011435

Submitter: G2P

Clinical Genomic Database (CGD)

Microcephaly 2, primary, autosomal recessive, with or without cortical malformationsAR

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: 10573015; 20729831; 20890279; 20890278; 21496009; 21834044; 21961505; 22308068; 23065275

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WDR62 variants in ClinVar

16 Conditions Cataloged

not providedTotal: 763

Inborn genetic diseasesTotal: 275

Microcephaly 2, primary, autosomal recessive, with or without cortical malformationsTotal: 268

not specifiedTotal: 135

WDR62-related disorderTotal: 66

Intellectual disabilityTotal: 6

Skraban-Deardorff syndromeTotal: 5

Autosomal recessive primary microcephalyTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001083961.2. 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		2 clinvar	20 clinvar	189 clinvar	6 clinvar	217
missense	3 clinvar	23 clinvar	440 clinvar	57 clinvar	5 clinvar	528
nonsense	15 clinvar	15 clinvar				30
start loss						0
frameshift	32 clinvar	29 clinvar	2 clinvar			63
splice donor/acceptor (+/-2bp)	5 clinvar	25 clinvar	9 clinvar			39
Total	55	94	471	246	11	877

Highest pathogenic variant AF is 0.00011971695

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 68 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001083961.2	RefSeq	NP_001077430.1	32	MANE Select
ENST00000401500.7	Ensembl	ENSP00000384792.1	32	MANE Select
NM_001411145.1	RefSeq	NP_001398074.1	32	Standard
NM_001411146.1	RefSeq	NP_001398075.1	30	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
wdr62	Danio rerio	Structure: retina Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

wdr62

Danio rerio

Structure: retina

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

mitotic spindle organization
centriole replication
cerebral cortex development
neurogenesis

Molecular Function

protein binding

Cellular Component

spindle pole
nucleus
centrosome
centriole
microtubule organizing center

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000401500
Coding exons: 32
Length: 50226
Individuals with no LoFs: 125629
Homozygous LoFs: 0
Heterozygous LoFs: 119
Defined: 125748
p: 0.000473

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.667	803	858	0.936	0.0000548	9851
Missense (PolyPhen)		234	299.97	0.78007		3607
Synonymous	-0.419	379	369	1.03	0.0000250	3087
Loss of Function	2.53	47	69.8	0.673	0.00000351	812

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00050	0.00049	rare
Latino/Admixed American	0.00099	0.00098	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00034	0.00033	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00040	0.00040	rare
South Asian	0.00056	0.00056	rare
Other	0.0010	0.00098	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Required for cerebral cortical development. Plays a role in neuronal proliferation and migration (PubMed:20890278, PubMed:20729831). Plays a role in mother-centriole-dependent centriole duplication; the function seems also to involve CEP152, CDK5RAP2 and CEP63 through a stepwise assembled complex at the centrosome that recruits CDK2 required for centriole duplication (PubMed:26297806). {ECO:0000269|PubMed:20729831, ECO:0000269|PubMed:20890278, ECO:0000269|PubMed:26297806}.;

Intolerance Scores

LoFtool: 0.892
RVIS EVS: 0.58
RVIS percentile EVS: 82.18

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.819

Gene Damage Prediction

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