Congenital myopathy 23

Summary

Congenital myopathy 23 (MONDO:0012240) is a disease caused by TPM2 (GenCC Strong), with 1 cohort gene.

At a glance

• Causal gene: TPM2 (GenCC Strong)
• Cohort genes: 1
• ClinVar variants: 43

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	congenital myopathy 23
Mondo ID	MONDO:0012240
MeSH	C538351
OMIM	609285
DOID	DOID:0110932
NCIT	C164225
UMLS	C1836447
MedGen	324513
GARD	0015454
Is cancer (heuristic)	no

Also known as: CAPM2 · NEM4 · nemaline myopathy 4 · nemaline myopathy caused by mutation in TPM2 · nemaline myopathy type 4 · TPM2 nemaline myopathy

Data availability: 43 ClinVar variants · 2 GenCC gene-disease records · 2 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › typical nemaline myopathy › congenital myopathy 23

Related subtypes (5): congenital myopathy 2a, typical, autosomal dominant, nemaline myopathy 2, nemaline myopathy 7, nemaline myopathy 9, nemaline myopathy 10

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

43 retrieved; paginated sample, class counts are floors:

19 uncertain significance, 7 conflicting classifications of pathogenicity, 6 benign, 4 pathogenic, 3 benign/likely benign, 2 pathogenic/likely pathogenic, 2 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
12462	NM_003289.4(TPM2):c.349G>A (p.Glu117Lys)	TPM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12464	NM_003289.4(TPM2):c.121G>A (p.Glu41Lys)	TPM2	Pathogenic	criteria provided, single submitter
12465	NM_003289.4(TPM2):c.412GAG[1] (p.Glu139del)	TPM2	Pathogenic	criteria provided, multiple submitters, no conflicts
12467	NM_003289.4(TPM2):c.606C>G (p.Asn202Lys)	TPM2	Pathogenic	no assertion criteria provided
140486	NM_003289.4(TPM2):c.14AGA[2] (p.Lys7del)	TPM2	Pathogenic	criteria provided, multiple submitters, no conflicts
977300	NM_003289.4(TPM2):c.782A>G (p.Tyr261Cys)	TPM2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
12466	NM_003289.4(TPM2):c.142AAG[1] (p.Lys49del)	TPM2	Likely pathogenic	criteria provided, single submitter
1299603	NM_213674.1(TPM2):c.773-2A>C	TPM2	Likely pathogenic	criteria provided, single submitter
224658	NM_003289.4(TPM2):c.181T>C (p.Ser61Pro)	TPM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
366766	NM_003289.4(TPM2):c.*25A>C	TPM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
366770	NM_003289.4(TPM2):c.564-9C>T	TPM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
366771	NM_003289.4(TPM2):c.-10C>A	TPM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
458723	NM_003289.4(TPM2):c.374+9G>C	TPM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
617588	NM_003289.4(TPM2):c.269G>A (p.Arg90His)	TPM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
914400	NM_003289.4(TPM2):c.558C>T (p.Ala186=)	TPM2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1028593	NM_003289.4(TPM2):c.773-5C>G	TPM2	Uncertain significance	criteria provided, single submitter
12461	NM_003289.4(TPM2):c.440A>C (p.Gln147Pro)	TPM2	Uncertain significance	criteria provided, single submitter
140496	NM_003289.4(TPM2):c.773-3C>A	TPM2	Uncertain significance	criteria provided, single submitter
2585480	NM_003289.4(TPM2):c.784G>T (p.Ala262Ser)	TPM2	Uncertain significance	criteria provided, single submitter
2627516	NM_003289.4(TPM2):c.144G>T (p.Lys48Asn)	TPM2	Uncertain significance	criteria provided, single submitter
2659179	NM_003289.4(TPM2):c.632C>T (p.Ala211Val)	TPM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
366765	NM_003289.4(TPM2):c.*99A>G	TPM2	Uncertain significance	criteria provided, single submitter
366773	NM_003289.4(TPM2):c.-92C>T	TPM2	Uncertain significance	criteria provided, single submitter
366774	NM_213674.1(TPM2):c.-158C>A	TPM2	Uncertain significance	criteria provided, single submitter
366775	NM_213674.1(TPM2):c.-238C>T	TPM2	Uncertain significance	criteria provided, multiple submitters, no conflicts
3775444	NM_003289.4(TPM2):c.23T>C (p.Met8Thr)	TPM2	Uncertain significance	criteria provided, single submitter
548556	NM_213674.1(TPM2):c.826C>G (p.Gln276Glu)	TPM2	Uncertain significance	criteria provided, single submitter
912915	NM_003289.4(TPM2):c.*22C>A	TPM2	Uncertain significance	criteria provided, single submitter
912958	NM_213674.1(TPM2):c.-142C>T	TPM2	Uncertain significance	criteria provided, single submitter
913283	NM_003289.4(TPM2):c.760G>A (p.Asp254Asn)	TPM2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 6 · 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
TPM2	Strong	Autosomal dominant	congenital myopathy 23	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TPM2	Orphanet:1146	Distal arthrogryposis type 1
TPM2	Orphanet:1147	Sheldon-Hall syndrome
TPM2	Orphanet:171436	Typical nemaline myopathy
TPM2	Orphanet:171439	Childhood-onset nemaline myopathy
TPM2	Orphanet:171881	Cap myopathy
TPM2	Orphanet:2020	Congenital fiber-type disproportion myopathy

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
TPM2	HGNC:12011	ENSG00000198467	P07951	Tropomyosin beta chain	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TPM2	Tropomyosin beta chain	Binds to actin filaments in muscle and non-muscle 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)
TPM2	Other/Unknown	no		Tropomyosin

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
blood vessel layer	1
popliteal artery	1
saphenous vein	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TPM2	283	ubiquitous	marker	saphenous vein, popliteal artery, blood vessel layer

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TPM2	357

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TPM2	P07951	91.51

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Striated Muscle Contraction	1	308.6×	0.004	TPM2
Smooth Muscle Contraction	1	265.6×	0.004	TPM2

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
regulation of ATP-dependent activity	1	8426.0×	4e-04	TPM2
muscle contraction	1	208.1×	0.007	TPM2
actin filament organization	1	118.7×	0.008	TPM2

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
TPM2	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	TPM2

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)
TPM2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.