WWP2

protein-coding

WW domain containing E3 ubiquitin protein ligase 2, the group of HECT domain containing|C2 and WW domain containing|MicroRNA protein coding host genes

Gene summary

This gene encodes a member of the Nedd4 family of E3 ligases, which play an important role in protein ubiquitination. The encoded protein contains four WW domains and may play a role in multiple processes including chondrogenesis and the regulation of oncogenic signaling pathways via interactions with Smad proteins and the tumor suppressor PTEN. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 10. [provided by RefSeq, Jul 2012]

MANE transcript

NM_001270454.2

Inheritance

—

ClinVar variants

U:135B:7

Top phenotype

Spondyloepiphyseal dysplasia, nishimura type

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr16:69,762,328-69,941,741

External References & Databases

Ensembl (ENSG00000198373)

Transcript & Mutation Effects

hg38 • Region Span ~179.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to WWP2 variants in ClinVar

4 Conditions Cataloged

not specifiedTotal: 118

not providedTotal: 6

Spondyloepiphyseal dysplasia, nishimura typeTotal: 1

Spondyloepiphyseal dysplasia MIR140 type NishimuraTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001270454.2. 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	4 clinvar	1 clinvar	7
missense			121 clinvar	2 clinvar		123
nonsense			2 clinvar			2
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			10 clinvar			10
Total	0	0	135	6	1	142

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 61 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001270454.2	RefSeq	NP_001257383.1	23	MANE Select
ENST00000359154.7	Ensembl	ENSP00000352069.2	23	MANE Select
NM_001270453.2	RefSeq	NP_001257382.1	20	Standard
NM_001270455.2	RefSeq	NP_001257384.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
wwp2	Danio rerio	Structure: palate Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

wwp2

Danio rerio

Structure: palate

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Ubiquitin mediated proteolysis - Homo sapiens (human)
Signal Transduction
Regulation of PTEN stability and activity
NOTCH3 Activation and Transmission of Signal to the Nucleus
Signaling by NOTCH3

Biological Process

negative regulation of transcription by RNA polymerase II
protein polyubiquitination
cellular protein modification process
ubiquitin-dependent protein catabolic process
extracellular transport

Molecular Function

RNA polymerase II transcription factor binding
ubiquitin-protein transferase activity
protein binding
transcription factor binding
ubiquitin protein ligase activity

Cellular Component

ubiquitin ligase complex
nucleus
cytoplasm
cytosol
membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359154
Coding exons: 23
Length: 179436
Individuals with no LoFs: 125675
Homozygous LoFs: 0
Heterozygous LoFs: 73
Defined: 125748
p: 0.000290

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.59	454	560	0.810	0.0000362	5677
Missense (PolyPhen)		187	285.12	0.65587		2832
Synonymous	0.591	211	222	0.950	0.0000151	1670
Loss of Function	5.21	13	54.5	0.238	0.00000272	576

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.0029	0.0029	notable
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000089	0.000088	rare
South Asian	0.000033	0.000033	rare
Other	0.00033	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Polyubiquitinates POU5F1 by 'Lys-63'-linked conjugation and promotes it to proteasomal degradation; in embryonic stem cells (ESCs) the ubiquitination is proposed to regulate POU5F1 protein level. Ubiquitinates EGR2 and promotes it to proteasomal degradation; in T-cells the ubiquitination inhibits activation- induced cell death. Ubiquitinates SLC11A2; the ubiquitination is enhanced by presence of NDFIP1 and NDFIP2. Ubiquitinates RPB1 and promotes it to proteasomal degradation. {ECO:0000269|PubMed:19274063, ECO:0000269|PubMed:19651900}.;

Recessive Scores

pRec: 0.137

Intolerance Scores

LoFtool: 0.366
RVIS EVS: -0.51
RVIS percentile EVS: 21.8

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.942

Gene Damage Prediction

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