Baraitser-winter syndrome 2

Summary

Baraitser-winter syndrome 2 (MONDO:0013812) is a disease caused by ACTG1 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: ACTG1 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 486

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	Baraitser-winter syndrome 2
Mondo ID	MONDO:0013812
OMIM	614583
DOID	DOID:0081113
UMLS	C3281235
MedGen	482865
GARD	0015817
Is cancer (heuristic)	no

Also known as: ACTG1 Baraitser-Winter cerebrofrontofacial syndrome · Baraitser-Winter cerebrofrontofacial syndrome caused by mutation in ACTG1 · Baraitser-winter syndrome 2 · Baraitser-Winter syndrome type 2 · BRWS2

Data availability: 486 ClinVar variants · 4 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › Baraitser-Winter cerebrofrontofacial syndrome › Baraitser-winter syndrome 2

Related subtypes (1): Baraitser-Winter 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

486 retrieved; paginated sample, class counts are floors:

265 likely benign, 97 uncertain significance, 37 benign/likely benign, 34 conflicting classifications of pathogenicity, 23 benign, 12 likely pathogenic, 9 pathogenic/likely pathogenic, 8 pathogenic, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1065444	NM_001614.5(ACTG1):c.209C>T (p.Pro70Leu)	ACTG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1483014	NM_001614.5(ACTG1):c.1013C>G (p.Ser338Trp)	ACTG1	Pathogenic	criteria provided, single submitter
18317	NM_001614.5(ACTG1):c.994C>G (p.Pro332Ala)	ACTG1	Pathogenic	criteria provided, single submitter
18322	NM_001614.5(ACTG1):c.721G>A (p.Glu241Lys)	ACTG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2444245	NM_001614.5(ACTG1):c.151G>A (p.Asp51Asn)	ACTG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29585	NM_001614.5(ACTG1):c.464C>T (p.Ser155Phe)	ACTG1	Pathogenic	criteria provided, multiple submitters, no conflicts
29586	NM_001614.5(ACTG1):c.359C>T (p.Thr120Ile)	ACTG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29587	NM_001614.5(ACTG1):c.404C>T (p.Ala135Val)	ACTG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29588	NM_001614.5(ACTG1):c.608C>A (p.Thr203Lys)	ACTG1	Pathogenic	no assertion criteria provided
29589	NM_001614.5(ACTG1):c.760C>T (p.Arg254Trp)	ACTG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
29590	NM_001614.5(ACTG1):c.766C>T (p.Arg256Trp)	ACTG1	Pathogenic	criteria provided, single submitter
505063	NM_001614.5(ACTG1):c.548G>A (p.Arg183Gln)	ACTG1	Pathogenic	criteria provided, multiple submitters, no conflicts
517300	NM_001614.5(ACTG1):c.617G>A (p.Arg206Gln)	ACTG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
520655	NM_001614.5(ACTG1):c.1004G>A (p.Arg335His)	ACTG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
807364	NM_001614.5(ACTG1):c.94C>T (p.Pro32Ser)	ACTG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
808333	NM_001614.5(ACTG1):c.547C>T (p.Arg183Trp)	ACTG1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
813525	NM_001614.5(ACTG1):c.628C>T (p.Arg210Cys)	ACTG1	Pathogenic	criteria provided, multiple submitters, no conflicts
1012294	NM_001614.5(ACTG1):c.439C>T (p.Arg147Cys)	ACTG1	Likely pathogenic	no assertion criteria provided
128266	NM_001614.5(ACTG1):c.598T>A (p.Phe200Ile)	ACTG1	Likely pathogenic	criteria provided, single submitter
1333817	NM_001614.5(ACTG1):c.459G>A (p.Met153Ile)	ACTG1	Likely pathogenic	criteria provided, single submitter
1994494	NM_001614.5(ACTG1):c.431C>T (p.Ala144Val)	ACTG1	Likely pathogenic	criteria provided, single submitter
2003119	NM_001614.5(ACTG1):c.188G>C (p.Gly63Ala)	ACTG1	Likely pathogenic	criteria provided, single submitter
2951653	NM_001614.5(ACTG1):c.714_716del (p.Lys238_Ser239delinsAsn)	ACTG1	Likely pathogenic	criteria provided, single submitter
3238813	NM_001614.5(ACTG1):c.95C>A (p.Pro32His)	ACTG1	Likely pathogenic	criteria provided, single submitter
374385	NM_001614.5(ACTG1):c.118C>T (p.His40Tyr)	ACTG1	Likely pathogenic	criteria provided, single submitter
3751495	NM_001614.5(ACTG1):c.442A>G (p.Thr148Ala)	ACTG1	Likely pathogenic	criteria provided, single submitter
452404	NM_001614.5(ACTG1):c.611C>G (p.Ala204Gly)	ACTG1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
473006	NM_001614.5(ACTG1):c.457A>G (p.Met153Val)	ACTG1	Likely pathogenic	criteria provided, single submitter
807363	NM_001614.5(ACTG1):c.728C>T (p.Pro243Leu)	ACTG1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1174527	NM_001614.5(ACTG1):c.826G>A (p.Glu276Lys)	ACTG1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 4 · 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
ACTG1	Definitive	Autosomal dominant	Baraitser-winter syndrome 2	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ACTG1	Orphanet:2995	Baraitser-Winter cerebrofrontofacial syndrome
ACTG1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
ACTG1	Orphanet:98942	Coloboma of choroid and retina
ACTG1	Orphanet:98944	Coloboma of iris

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
ACTG1	HGNC:144	ENSG00000184009	P63261	Actin, cytoplasmic 2	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ACTG1	Actin, cytoplasmic 2	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.

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)
ACTG1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS

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
amniotic fluid	1
ileal mucosa	1
ventricular zone	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ACTG1	288	ubiquitous	marker	ileal mucosa, ventricular zone, amniotic fluid

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACTG1	1,017

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTG1	P63261	10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 69. 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
Formation of annular gap junctions	1	1038.2×	0.010	ACTG1
GBP-mediated host defense	1	1038.2×	0.010	ACTG1
Gap junction degradation	1	951.7×	0.010	ACTG1
Regulation of CDH1 Function	1	951.7×	0.010	ACTG1
RHOBTB GTPase Cycle	1	815.7×	0.010	ACTG1
Cell-extracellular matrix interactions	1	671.8×	0.010	ACTG1
Gap junction trafficking and regulation	1	475.8×	0.010	ACTG1
Gap junction trafficking	1	475.8×	0.010	ACTG1
RHOBTB2 GTPase cycle	1	475.8×	0.010	ACTG1
Signaling by RAS mutants	1	423.0×	0.010	ACTG1
Interaction between L1 and Ankyrins	1	368.4×	0.010	ACTG1
RHO GTPases activate IQGAPs	1	346.1×	0.010	ACTG1
Parasite infection	1	346.1×	0.010	ACTG1
Leishmania phagocytosis	1	346.1×	0.010	ACTG1
RHO GTPases Activate WASPs and WAVEs	1	317.2×	0.010	ACTG1
Signaling by high-kinase activity BRAF mutants	1	317.2×	0.010	ACTG1
Sensory processing of sound	1	308.6×	0.010	ACTG1
Formation of the dystrophin-glycoprotein complex (DGC)	1	308.6×	0.010	ACTG1
MAP2K and MAPK activation	1	285.5×	0.010	ACTG1
Fcgamma receptor (FCGR) dependent phagocytosis	1	278.5×	0.010	ACTG1
Signaling by RAF1 mutants	1	278.5×	0.010	ACTG1
EPHB-mediated forward signaling	1	265.6×	0.010	ACTG1
Signaling by moderate kinase activity BRAF mutants	1	253.8×	0.010	ACTG1
Paradoxical activation of RAF signaling by kinase inactive BRAF	1	253.8×	0.010	ACTG1
Signaling downstream of RAS mutants	1	253.8×	0.010	ACTG1
Adherens junctions interactions	1	248.3×	0.010	ACTG1
Cell-cell junction organization	1	248.3×	0.010	ACTG1
Oncogenic MAPK signaling	1	248.3×	0.010	ACTG1
Recycling pathway of L1	1	223.9×	0.010	ACTG1
Signaling by VEGF	1	219.6×	0.010	ACTG1

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
morphogenesis of a polarized epithelium	1	4213.0×	0.002	ACTG1
regulation of transepithelial transport	1	4213.0×	0.002	ACTG1
protein localization to bicellular tight junction	1	2808.7×	0.002	ACTG1
tight junction assembly	1	2407.4×	0.002	ACTG1
regulation of stress fiber assembly	1	991.3×	0.003	ACTG1
regulation of synaptic vesicle endocytosis	1	887.0×	0.003	ACTG1
regulation of focal adhesion assembly	1	601.9×	0.004	ACTG1
positive regulation of wound healing	1	526.6×	0.004	ACTG1
maintenance of blood-brain barrier	1	481.5×	0.004	ACTG1
cell motility	1	401.2×	0.004	ACTG1
sarcomere organization	1	383.0×	0.004	ACTG1
platelet aggregation	1	337.0×	0.004	ACTG1
cellular response to type II interferon	1	208.1×	0.006	ACTG1
axonogenesis	1	160.5×	0.008	ACTG1
angiogenesis	1	62.4×	0.017	ACTG1
positive regulation of cell migration	1	61.7×	0.017	ACTG1
positive regulation of gene expression	1	38.7×	0.026	ACTG1

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
ACTG1	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	ACTG1

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)
ACTG1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.