Nemaline myopathy 2

Summary

Nemaline myopathy 2 (MONDO:0009725) is a disease caused by NEB (GenCC Definitive), with 5 cohort genes.

At a glance

• Causal gene: NEB (GenCC Definitive)
• Cohort genes: 5
• ClinVar variants: 11,200

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	nemaline myopathy 2
Mondo ID	MONDO:0009725
MeSH	C538349
OMIM	256030
DOID	DOID:0110928
NCIT	C118784
UMLS	C1850569
MedGen	342534
GARD	0015209
Is cancer (heuristic)	no

Also known as: NEB nemaline myopathy · NEM2 · nemaline myopathy 2 · nemaline myopathy caused by mutation in NEB · nemaline myopathy type 2

Data availability: 11,200 ClinVar variants · 5 GenCC gene-disease records · 24 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › severe congenital nemaline myopathy › nemaline myopathy 2

Related subtypes (4): congenital myopathy 2a, typical, autosomal dominant, nemaline myopathy 8, 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

600 retrieved; paginated sample, class counts are floors:

337 likely benign, 147 uncertain significance, 48 pathogenic, 27 pathogenic/likely pathogenic, 24 conflicting classifications of pathogenicity, 16 likely pathogenic, 1 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1027398	NM_001164508.2(NEB):c.24766-1G>C	NEB	Pathogenic	no assertion criteria provided
1030244	NM_001164508.2(NEB):c.13285G>T (p.Glu4429Ter)	NEB	Pathogenic	criteria provided, single submitter
1031200	NM_001164508.2(NEB):c.5388T>A (p.Tyr1796Ter)	NEB	Pathogenic	criteria provided, single submitter
1066812	NM_001164508.2(NEB):c.1570-2del	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068014	NM_001164508.2(NEB):c.928-1G>A	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068018	NM_001164508.2(NEB):c.2836-2A>G	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068470	NM_001164508.2(NEB):c.24003_24006dup (p.Glu8003fs)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068585	NM_001164508.2(NEB):c.12074del (p.Ser4025fs)	NEB	Pathogenic	criteria provided, single submitter
1068855	NM_001164508.2(NEB):c.22044_22045del (p.Val7348_Ser7349insTer)	NEB	Pathogenic	criteria provided, single submitter
1069231	NM_001164508.2(NEB):c.8386del (p.Glu2796fs)	NEB	Pathogenic	criteria provided, single submitter
1069319	NM_001164508.2(NEB):c.3843del (p.Leu1282fs)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1069433	NM_001164508.2(NEB):c.25003A>T (p.Lys8335Ter)	NEB	Pathogenic	criteria provided, single submitter
1069477	NC_000002.11:g.(?152524298)(152525665_?)del	NEB	Pathogenic	criteria provided, single submitter
1069703	NM_001164508.2(NEB):c.13173T>A (p.Tyr4391Ter)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070630	NM_001164508.2(NEB):c.2075_2076del (p.His692fs)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070695	NM_001164508.2(NEB):c.17373C>A (p.Cys5791Ter)	NEB	Pathogenic	criteria provided, single submitter
1070706	NM_001164508.2(NEB):c.611del (p.Lys204fs)	NEB	Pathogenic	criteria provided, single submitter
1070917	NM_001164508.2(NEB):c.5229dup (p.Met1744fs)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071068	NM_001164508.2(NEB):c.19156G>T (p.Glu6386Ter)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071128	NM_001164508.2(NEB):c.63del (p.Glu22fs)	NEB	Pathogenic	criteria provided, single submitter
1071130	NM_001164508.2(NEB):c.6639del (p.Phe2213fs)	NEB	Pathogenic	criteria provided, single submitter
1071142	NM_001164508.2(NEB):c.12736del (p.Ile4246fs)	NEB	Pathogenic	criteria provided, single submitter
1071192	NM_001164508.2(NEB):c.13099G>T (p.Gly4367Ter)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071337	NM_001164508.2(NEB):c.288del (p.Phe96fs)	NEB	Pathogenic	criteria provided, single submitter
1071349	NM_001164508.2(NEB):c.1083T>A (p.Tyr361Ter)	NEB	Pathogenic	criteria provided, single submitter
1071472	NM_001164508.2(NEB):c.19915del (p.Ala6639fs)	NEB	Pathogenic	criteria provided, single submitter
1071473	NM_001164508.2(NEB):c.175C>T (p.Gln59Ter)	NEB	Pathogenic	criteria provided, multiple submitters, no conflicts
1071773	NM_001164508.2(NEB):c.9840C>G (p.Tyr3280Ter)	NEB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1071818	NM_001164508.2(NEB):c.24077_24084del (p.Met8026fs)	NEB	Pathogenic	criteria provided, single submitter
1071929	NM_001164508.2(NEB):c.13417del (p.Leu4473fs)	NEB	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 16 · 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
NEB	Definitive	Autosomal recessive	nemaline myopathy 2	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NEB	Orphanet:171430	Severe congenital nemaline myopathy
NEB	Orphanet:171433	Intermediate nemaline myopathy
NEB	Orphanet:171436	Typical nemaline myopathy
NEB	Orphanet:171439	Childhood-onset nemaline myopathy
NEB	Orphanet:33108	Lethal multiple pterygium syndrome
NEB	Orphanet:399103	Autosomal recessive distal nebulin myopathy
NEB	Orphanet:708123	Autosomal dominant distal nebulin myopathy
ACTA1	Orphanet:171430	Severe congenital nemaline myopathy
ACTA1	Orphanet:171433	Intermediate nemaline myopathy
ACTA1	Orphanet:171436	Typical nemaline myopathy
ACTA1	Orphanet:171439	Childhood-onset nemaline myopathy
ACTA1	Orphanet:2020	Congenital fiber-type disproportion myopathy
ACTA1	Orphanet:447977	Progressive scapulohumeroperoneal distal myopathy
ACTA1	Orphanet:97240	Zebra body myopathy
ACTA1	Orphanet:97244	Rigid spine syndrome
ACTA1	Orphanet:98904	Congenital myopathy with excess of thin filaments

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NEB	HGNC:7720	ENSG00000183091	P20929	Nebulin	gencc,clinvar
ACTA1	HGNC:129	ENSG00000143632	P68133	Actin, alpha skeletal muscle	clinvar
RIF1	HGNC:23207	ENSG00000080345	Q5UIP0	Telomere-associated protein RIF1	clinvar
LRIF1	HGNC:30299	ENSG00000121931	Q5T3J3	Ligand-dependent nuclear receptor-interacting factor 1	clinvar
ARL5A	HGNC:696	ENSG00000162980	Q9Y689	ADP-ribosylation factor-like protein 5A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NEB	Nebulin	This giant muscle protein may be involved in maintaining the structural integrity of sarcomeres and the membrane system associated with the myofibrils.
ACTA1	Actin, alpha skeletal muscle	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
RIF1	Telomere-associated protein RIF1	Key regulator of TP53BP1 that plays a key role in the repair of double-strand DNA breaks (DSBs) in response to DNA damage: acts by promoting non-homologous end joining (NHEJ)-mediated repair of DSBs.
LRIF1	Ligand-dependent nuclear receptor-interacting factor 1	Together with SMCHD1, involved in chromosome X inactivation in females by promoting the compaction of heterochromatin.
ARL5A	ADP-ribosylation factor-like protein 5A	Lacks ADP-ribosylation enhancing activity.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 4 · 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
Scaffold/PPI	1	3.5×	0.269
Other/Unknown	4	1.4×	0.269

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NEB	Scaffold/PPI	no		Nebulin_repeat, SH3_domain, Nebulin-like
ACTA1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
RIF1	Other/Unknown	no		ARM-like, ARM-type_fold, Rif1_N
LRIF1	Other/Unknown	no		LRIF1
ARL5A	Other/Unknown	no		Small_GTP-bd, Small_GTPase_ARF/SAR, Small_GTPase_ARF

Expression context

Cohort genes with no expression data: 0.

5 cohort genes 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gluteal muscle	2
calcaneal tendon	2
biceps brachii	1
tibialis anterior	1
diaphragm	1
skeletal muscle tissue of biceps brachii	1
buccal mucosa cell	1
gastrocnemius	1
hindlimb stylopod muscle	1
male germ line stem cell (sensu Vertebrata) in testis	1
primordial germ cell in gonad	1
nipple	1
upper arm skin	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NEB	204	tissue_specific	marker	gluteal muscle, tibialis anterior, biceps brachii
ACTA1	203	broad	marker	gluteal muscle, skeletal muscle tissue of biceps brachii, diaphragm
RIF1	279	ubiquitous	marker	buccal mucosa cell, gastrocnemius, hindlimb stylopod muscle
LRIF1	271	ubiquitous	marker	calcaneal tendon, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
ARL5A	260	ubiquitous	marker	calcaneal tendon, nipple, upper arm skin

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ARL5A	2,461
RIF1	2,384
NEB	1,402
LRIF1	1,295
ACTA1	523

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ACTA1	P68133	5
ARL5A	Q9Y689	4
NEB	P20929	3
RIF1	Q5UIP0	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRIF1	Q5T3J3	48.88

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 5 evidence-associated genes (3 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 3 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	2	205.8×	2e-04	NEB, ACTA1
Muscle contraction	2	51.4×	0.002	NEB, ACTA1
Regulation of CDH1 Function	1	317.2×	0.008	ACTA1
Formation of the dystrophin-glycoprotein complex (DGC)	1	102.9×	0.019	ACTA1
Nonhomologous End-Joining (NHEJ)	1	56.0×	0.022	RIF1
Activation of STAT3 by cadherin engagement	1	54.4×	0.022	ACTA1
Non-integrin membrane-ECM interactions	1	51.4×	0.022	ACTA1
Extracellular matrix organization	1	21.0×	0.047	ACTA1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
cardiac muscle thin filament assembly	1	1123.5×	0.009	NEB
somatic muscle development	1	842.6×	0.009	NEB
regulation of actin filament length	1	842.6×	0.009	NEB
mesenchyme migration	1	674.1×	0.009	ACTA1
skeletal muscle thin filament assembly	1	561.7×	0.009	ACTA1
protein localization to Golgi membrane	1	421.3×	0.009	ARL5A
telomere maintenance in response to DNA damage	1	374.5×	0.009	RIF1
dosage compensation by inactivation of X chromosome	1	306.4×	0.009	LRIF1
subtelomeric heterochromatin formation	1	306.4×	0.009	RIF1
positive regulation of isotype switching	1	259.3×	0.010	RIF1
positive regulation of double-strand break repair via nonhomologous end joining	1	198.3×	0.012	RIF1
negative regulation of double-strand break repair via homologous recombination	1	124.8×	0.017	RIF1
skeletal muscle fiber development	1	108.7×	0.018	ACTA1
negative regulation of gene expression, epigenetic	1	80.2×	0.023	RIF1
telomere maintenance	1	53.5×	0.032	RIF1
somatic stem cell population maintenance	1	49.6×	0.033	RIF1
muscle contraction	1	41.6×	0.036	ACTA1
muscle organ development	1	33.4×	0.043	NEB
cellular response to leukemia inhibitory factor	1	31.8×	0.043	RIF1
vesicle-mediated transport	1	19.3×	0.066	ARL5A
intracellular protein transport	1	13.0×	0.090	ARL5A
DNA repair	1	12.8×	0.090	RIF1
DNA damage response	1	10.7×	0.102	RIF1
positive regulation of gene expression	1	7.8×	0.133	ACTA1
regulation of DNA-templated transcription	1	6.3×	0.155	LRIF1
negative regulation of transcription by RNA polymerase II	1	3.5×	0.252	RIF1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RIF1	1	2
NEB	0	0
ACTA1	0	0
LRIF1	0	0
ARL5A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	RIF1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RIF1	7	Binding:7

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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.

Compound	Max phase	Cohort target (bioactivity)
MOLIBRESIB	2	RIF1

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	1	RIF1
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	NEB, ACTA1, LRIF1, ARL5A

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NEB	0	—
ACTA1	0	—
LRIF1	0	—
ARL5A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.