Townes-Brocks syndrome 2

Summary

Townes-Brocks syndrome 2 (MONDO:0054582) is a disease with 1 cohort gene.

At a glance

• Cohort genes: 1
• ClinVar variants: 17

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Townes-Brocks syndrome 2
Mondo ID	MONDO:0054582
OMIM	617466
UMLS	C4479534
MedGen	1381939
GARD	0025952
Is cancer (heuristic)	no

Also known as: TBS2 · Townes-Brocks syndrome 2

Data availability: 17 ClinVar variants · 5 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › Townes-Brocks syndrome › Townes-Brocks syndrome 2

Related subtypes (1): Townes-Brocks syndrome 1

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

17 retrieved; paginated sample, class counts are floors:

6 uncertain significance, 5 pathogenic, 2 benign, 2 conflicting classifications of pathogenicity, 1 likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
2443964	NM_001079520.2(DACT1):c.1592G>A (p.Arg531Lys)	DACT1	Pathogenic	no assertion criteria provided
2443965	NM_001079520.2(DACT1):c.1660C>T (p.Leu554Phe)	DACT1	Pathogenic	no assertion criteria provided
2443966	NM_001079520.2(DACT1):c.2357T>G (p.Leu786Arg)	DACT1	Pathogenic	no assertion criteria provided
2443967	NM_001079520.2(DACT1):c.1779G>T (p.Lys593Asn)	DACT1	Pathogenic	no assertion criteria provided
424859	NM_001079520.2(DACT1):c.1145G>A (p.Trp382Ter)	DACT1	Pathogenic	no assertion criteria provided
3899992	NM_001079520.2(DACT1):c.763C>T (p.Leu255=)	DACT1	Likely pathogenic	no assertion criteria provided
739044	NM_001079520.2(DACT1):c.989C>A (p.Thr330Lys)	DACT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
782307	NM_001079520.2(DACT1):c.930G>C (p.Gln310His)	DACT1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1709329	NM_001079520.2(DACT1):c.2122G>A (p.Glu708Lys)	DACT1	Uncertain significance	criteria provided, single submitter
3242040	NM_001079520.2(DACT1):c.1703C>T (p.Thr568Met)	DACT1	Uncertain significance	criteria provided, single submitter
3499556	NM_001079520.2(DACT1):c.1353G>C (p.Glu451Asp)	DACT1	Uncertain significance	criteria provided, multiple submitters, no conflicts
4078455	NM_001079520.2(DACT1):c.1128C>G (p.Phe376Leu)	DACT1	Uncertain significance	criteria provided, single submitter
4847007	NM_001079520.2(DACT1):c.1168_1177del (p.Gln390fs)	DACT1	Uncertain significance	criteria provided, single submitter
982996	NM_001079520.2(DACT1):c.2207C>T (p.Thr736Ile)	DACT1	Uncertain significance	criteria provided, single submitter
1255447	NM_001079520.2(DACT1):c.268C>T (p.Leu90=)	DACT1	Benign	criteria provided, multiple submitters, no conflicts
1255448	NM_001079520.2(DACT1):c.1280C>T (p.Ala427Val)	DACT1	Benign	criteria provided, multiple submitters, no conflicts
724606	NM_001079520.2(DACT1):c.769G>A (p.Glu257Lys)	DACT1	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 3 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
DACT1	Moderate	Autosomal dominant	Townes-Brocks syndrome 2	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DACT1	Orphanet:268823	Occipital encephalocele
DACT1	Orphanet:63260	Craniorachischisis
DACT1	Orphanet:857	Townes-Brocks syndrome

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DACT1	HGNC:17748	ENSG00000165617	Q9NYF0	Dapper homolog 1	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DACT1	Dapper homolog 1	Involved in regulation of intracellular signaling pathways during development.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	1	1.8×	0.558

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DACT1	Other/Unknown	no		Dapper

Expression context

Cohort genes with no expression data: 0.

1 cohort gene are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
gall bladder	1
right coronary artery	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DACT1	200	ubiquitous	marker	cortical plate, right coronary artery, gall bladder

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DACT1	1,107

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 0

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
DACT1	Q9NYF0	50.95

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 1 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Degradation of DVL	1	237.9×	0.004	DACT1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
embryonic hindgut morphogenesis	1	5617.3×	0.001	DACT1
negative regulation of beta-catenin-TCF complex assembly	1	5617.3×	0.001	DACT1
regulation of Wnt signaling pathway, planar cell polarity pathway	1	3370.4×	0.001	DACT1
negative regulation of JNK cascade	1	561.7×	0.005	DACT1
regulation of canonical Wnt signaling pathway	1	543.6×	0.005	DACT1
neural tube development	1	526.6×	0.005	DACT1
positive regulation of Wnt signaling pathway	1	383.0×	0.005	DACT1
negative regulation of G1/S transition of mitotic cell cycle	1	358.6×	0.005	DACT1
negative regulation of Wnt signaling pathway	1	343.9×	0.005	DACT1
positive regulation of protein catabolic process	1	203.0×	0.007	DACT1
positive regulation of canonical Wnt signaling pathway	1	154.6×	0.009	DACT1
regulation of protein stability	1	125.8×	0.010	DACT1
negative regulation of canonical Wnt signaling pathway	1	117.8×	0.010	DACT1
Wnt signaling pathway	1	99.7×	0.011	DACT1
negative regulation of transcription by RNA polymerase II	1	17.7×	0.056	DACT1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 1

Druggability breadth: 0 of 1 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DACT1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	DACT1

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
DACT1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.