WWC2

Chr 4

WW and C2 domain containing 2

Also known as: BOMB

NCBI Gene: 80014 ENSG00000151718 UniProt: Q6AWC2 OMIM: 620110

The protein regulates the Hippo signaling pathway by enhancing phosphorylation of LATS1 and YAP1, thereby suppressing cell proliferation and organ growth through inhibition of YAP1 transcriptional activity. Mutations cause autosomal recessive intellectual disability with microcephaly and seizures, typically presenting in early childhood. The gene shows minimal constraint against loss-of-function variants, consistent with its recessive inheritance pattern.

OMIM ResearchSummary from RefSeq, UniProt

This gene encodes a member of the WW-and-C2-domain-containing family of proteins. Members of this family have two N-terminal WW domains that mediate binding to target proteins harboring L/PPxY motifs, an internal C2 domain for membrane association, and C-terminal alpha protein kinase C binding sites and class III PDZ domain-interaction motifs. Proteins of this family are able to form homo- and heterodimers and to modulate hippo pathway signaling. [provided by RefSeq, Sep 2016]

OMIM ResearchGenerating clinical summary…

DNmechanismLOEUF 0.55

Clinical Summary— WWC2

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

189 VUS of 230 total submissions

Explore recent and relevant literature in Research Assistant →

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.55LOEUF

pLI 0.000

Z-score 4.27

OE 0.39 (0.28–0.55)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

0.34Z-score

OE missense 0.96 (0.90–1.03)

574 obs / 597.5 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.39 (0.28–0.55)

0≤0.351.4

Missense OE?0.96 (0.90–1.03)

0≤0.61.4

Synonymous OE?1.04

0≤1.21.6

LoF obs/exp: 22 / 56.7Missense obs/exp: 574 / 597.5Syn Z: -0.47

This gene — mechanism propensity

0.6745th %ile

GOF

0.6053th %ile

LOF

0.3843th %ile

The highest-scoring mechanism for this gene is dominant-negative.

DNprediction above median

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

ClinVar Variant Classifications

230 submitted variants in ClinVar

ClinVar

Classification Summary

VUS189

Likely Benign12

Benign2

189

VUS

Likely Benign

Benign

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	Missense + Inframe	Synonymous	Total
Pathogenic	0	0	0
Likely Pathogenic	0	0	0
VUS	189	0	189
Likely Benign	10	2	12
Benign	0	2	2
Total	199	4	203

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

103 pathogenic / likely-pathogenic (of 117) ClinVar copy-number / structural variants overlap WWC2 — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →