NEB
protein-codingnebulin
Gene summary
This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]
- NEM2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~249.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009725
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0015735
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009725
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009725
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0015738
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015737
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0015736
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009725
Submitter: Natera
Inheritance Pattern: AR
Disease ID:MONDO:0009668
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:1010152
Submitter: ClinGen
Variants in *NEB* have been reported in individuals with the following disease entities: autosomal recessive nemaline myopathy and autosomal dominant nebulin-related myopathy. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism and inheritance pattern. Therefore, the following disease entities have been split into multiple disease entities: autosomal recessive nemaline myopathy (MONDO:0009725) and autosomal dominant nebulin-related myopathy (MONDO:1010152). The split curation for autosomal recessive nemaline myopathy has been previously curated. *NEB* was FIRST reported in relation to autosomal dominant nebulin-related myopathy (MONDO:1010152) in 2019 when Kiiski and colleagues described a three-generational non-sanguineous Finnish family affected with autosomal dominantly inherited distal nemaline/cap myopathy while harboring a large in-frame deletion spanning exons 14 to 89 of the NEB gene (PMID: 30679003). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Large in-frame deletions in this gene have been reported in at least twelve probands in two publications (PMID: 30679003, 33933294) and in one manuscript preprint (PMID: 39802796). This gene-disease relationship is supported by animal and non-human cell models, expression studies, and in vitro functional assays (PMID: 11309420, 12064939, 165157704, 20498015, 23375831, 23715323, 25110572). Bulk tissue gene expression data from the GTEx Portal indicates *NEB* is highly expressed in skeletal muscle (PMID: 23715323, dbGaP Accession phs000424.v10.p2). Two-hybrid screening and protein pull down assays show interactions with proteins having similar roles in maintenance of muscle structure and function and previously implicated in muscloskeletal system disorders (PMID: 11309420, 12064939, 25110572). RNAi knockdown of *NEB* in rat fetal myocytes corresponded to reduced nebulin levels and nonstriated appearance of thin filament components (PMID: 16157704). Nebulin heterozygous mice model studies showed slight reduction in muscle force (PMID: 23375831). Studies involving chick skeletal myocytes transfected with shorter version of human nebulin showed the synthetic mini-nebulin can undergo successful transcription and translation as well as stabilize actin filaments within the confines of their short length (PMID: 20498015). Similarly, Western blot analysis shows truncated nebulin isoforms present in affected patients with in-frame deletions in *NEB* (PMID: 30679003, 33933294). In summary, there is moderate evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Congenital Myopathies Gene Curation Expert Panel on March 11, 2025 (SOP version 11).
Inheritance Pattern: AR
Disease ID:MONDO:0009725
Submitter: Myriad Women's Health
Inheritance Pattern: AD
Disease ID:MONDO:0009725
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0009725
Submitter: ClinGen
The relationship between NEB and Nemaline Myopathy 2 (Autosomal Recessive) was evaluated using the ClinGen Clinical Validity Framework as of 09/09/19. Variants in NEB were first reported in humans with this disease as early as 1999 (Pelin et al. 1999, PMID: 10051637). At least 17 variants (e.g. missense, nonsense, frameshift) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 11 probands in 3 publications (PMIDs: 30517146, 10051637, 27105866). Of note is that all curated probands have at least one predicted null variant. Much more evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism for disease is homozygous loss of function, with the lack of actin organization contributing to skeletal muscle degradation and disorganization as well as the reduced contractile strength and calcium sensitivity causing muscle weakness and other related symptoms. This gene-disease association is supported by two separate mouse models, each recapitulating the base phenotype of the disorder. There are several other pieces of functional evidence, most notably the interactions with KLHL40, the actin-binding function of the protein, expression primarily in the muscle, and cultured muscle fiber cells showing reduced contractile strength compared to controls. There is more experimental evidence available, but the maximum has been reached. In summary, NEB is definitively associated with Autosomal Recessive Nemaline Myopathy 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Congenital Myopathy Working Group on 10/21/19. (SOP Version 7).
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to NEB variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001164508.2. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 4 | 10 | 116 | 3344 | 72 | 3546 |
| missense | 4 | 53 | 2955 | 1245 | 38 | 4295 |
| nonsense | 196 | 347 | 10 | 553 | ||
| start loss | 0 | |||||
| frameshift | 331 | 592 | 5 | 928 | ||
| splice donor/acceptor (+/-2bp) | 39 | 404 | 27 | 1 | 471 | |
| Total | 574 | 1406 | 3113 | 4590 | 110 | 9793 |
Highest pathogenic variant AF is 0.0011467724
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001157980.2 | 180 | MANE Select | |
| Ensembl | ENSP00000380505.3 | 180 | MANE Select | |
| RefSeq | NP_001157979.2 | 180 | MANE Plus Clinical | |
| RefSeq | NP_001258137.2 | 181 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| neb | Danio rerio | Structure: skeletal muscle cell Quality: aggregated abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Striated Muscle Contraction
- Factors and pathways affecting insulin-like growth factor (IGF1)-Akt signaling
- Striated Muscle Contraction
- Muscle contraction
Biological Process
- muscle organ development
- somatic muscle development
- muscle filament sliding
- regulation of actin filament length
- muscle fiber development
Molecular Function
- protein binding
- structural constituent of muscle
- actin filament binding
Cellular Component
- cytosol
- actin cytoskeleton
- Z disc
- extracellular exosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000397345
- Coding exons
- 180
- Length
- 249152
- Individuals with no LoFs
- 124483
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 365
- Defined
- 124848
- p
- 0.00146
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.0409 | 3782 | 3.77e+3 | 1.00 | 0.000208 | 56792 |
| Missense (PolyPhen) | 1817 | 1893.8 | 0.95943 | 28149 | ||
| Synonymous | -0.364 | 1373 | 1.36e+3 | 1.01 | 0.0000788 | 14549 |
| Loss of Function | 11.6 | 145 | 393 | 0.369 | 0.0000205 | 5971 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0015 | 0.0014 | notable |
| Latino/Admixed American | 0.0015 | 0.0014 | notable |
| Ashkenazi Jewish | 0.00090 | 0.00079 | rare |
| East Asian | 0.0014 | 0.0013 | notable |
| Finnish | 0.00098 | 0.00097 | rare |
| European (Non-Finnish) | 0.0018 | 0.0017 | notable |
| South Asian | 0.0014 | 0.0014 | notable |
| Other | 0.0017 | 0.0016 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: This giant muscle protein may be involved in maintaining the structural integrity of sarcomeres and the membrane system associated with the myofibrils. Binds and stabilize F-actin.;
Recessive Scores
- pRec
- 0.379
Intolerance Scores
- LoFtool
- 0.995
- RVIS EVS
- 0.88
- RVIS percentile EVS
- 88.9
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.744
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |