NEB

Chr 2AR

nebulin

Also known as: AMC6, NEB177D, NEM2

NCBI Gene: 4703ENSG00000183091UniProt: P20929

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]

Primary Disease Associations & Inheritance

Arthrogryposis multiplex congenita 6MIM #619334
AR
Nemaline myopathy 2, autosomal recessiveMIM #256030
AR
561
ClinVar variants
46
Pathogenic / LP
0.00
pLI score
2
Active trials
Clinical Summary— NEB
🧬
Gene-Disease Validity (ClinGen)
nemaline myopathy 2 · ARDefinitive

Definitive — sufficient evidence for diagnostic panels

2 total gene-disease associations curated

⚡
Population Constraint (gnomAD)
Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.
📋
ClinVar Variants
46 Pathogenic / Likely Pathogenic· 369 VUS of 561 total submissions
💊
Clinical Trials
2 active or recruiting trials — potential therapeutic options may be available

Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD
Moderate LoF intolerance
LoF Constraint?LOEUF (Loss-of-function Observed/Expected Upper bound Fraction) is the upper bound of the 90% CI for LoF OE — the preferred gnomAD v4 metric. Lower = more intolerant to LoF. LOEUF < 0.35 = highly constrained.
0.42LOEUF
pLI 0.000
Z-score 11.58
OE 0.37 (0.32–0.42)
Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?Missense Z-score: standard deviations fewer missense variants observed vs. expected. Z > 3.09 (p < 0.001) = gene does not tolerate missense variation. OE missense < 0.6 is also considered constrained.
-0.04Z-score
OE missense 1.00 (0.97–1.03)
3782 obs / 3774.9 exp
Tolerant

Tolerant to missense variation

Observed / Expected Ratios?Shaded band = 90% confidence interval. Vertical tick = point estimate. Grey threshold line = gnomAD constraint cutoff for that variant class.
LoF OE?Ratio of observed to expected LoF variants. Upper CI bound (LOEUF) ≤ 0.35 = strong LoF constraint signal.0.37 (0.32–0.42)
0≤0.351.4
Missense OE?Ratio of observed to expected missense variants. OE ≤ 0.6 = fewer missense variants than expected by chance.1.00 (0.97–1.03)
0≤0.61.4
Synonymous OE?Control metric — synonymous variants are largely neutral and expected near OE = 1.0. Significant deviation may indicate annotation issues.1.01
0≤1.21.6
LoF obs/exp: 145 / 392.5Missense obs/exp: 3782 / 3774.9Syn Z: -0.36

ClinVar Variant Classifications

561 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic17
Likely Pathogenic29
VUS369
Likely Benign143
Benign2
Conflicting1
17
Pathogenic
29
Likely Pathogenic
369
VUS
143
Likely Benign
2
Benign
1
Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

ClassificationLoFMissense + InframeNon-codingSynonymousTotal
Pathogenic
11
0
6
0
17
Likely Pathogenic
21
0
8
0
29
VUS
0
295
37
37
369
Likely Benign
0
6
75
62
143
Benign
0
0
2
0
2
Conflicting
—1
Total3230112899561

LoF = frameshift, stop gained/lost, canonical splice · Counts from ClinVar esearch · Updated hourly

View in ClinVar →

Protein Context — Lollipop Plot

NEB · protein map & ClinVar variants

Showing all ClinVar variants across the protein. Search a specific variant to highlight its position.

Gene2Phenotype Curations

NEB-related typical nemaline myopathy

definitive
ARLoss Of FunctionAbsent Gene Product
Dev. Disorders
G2P ↗

Gene2Phenotype curations · DECIPHER consortium patient cohort (public variants) · deciphergenomics.org

OMIM — Genotype-Phenotype Relationships

1 OMIM entry

OMIM
NEBULIN; NEB
MIM #161650 · *

Arthrogryposis multiplex congenita 6

MIM #619334

Molecular basis of disorder known

Autosomal recessive

Nemaline myopathy 2, autosomal recessive

MIM #256030

Molecular basis of disorder known

Autosomal recessive
📖
GeneReview available — NEB
Authoritative clinical overview · NCBI Bookshelf · Recommended first read
Open GeneReview ↗
Clinical Literature
Landmark / reviewRecent case evidence
Key Publications
Landmark & review papers · by relevance
PubMed
Panorama of the distal myopathies.
Savarese M et al.·Acta Myol
2020Review
Long-read sequencing improves diagnostic rate in neuromuscular disorders.
Owusu R et al.·Acta Myol
2023Review
Mutation update: the spectra of nebulin variants and associated myopathies.
Lehtokari VL et al.·Hum Mutat
2014
Delineation of dominant and recessive forms of LZTR1-associated Noonan syndrome.
Pagnamenta AT et al.·Clin Genet
2019Case report
Targeted Next-Generation Sequencing in a Large Cohort of Genetically Undiagnosed Patients with Neuromuscular Disorders in Spain.
Gonzalez-Quereda L et al.·Genes (Basel)
2020Cohort
Metagenomics next-generation sequencing tests take the stage in the diagnosis of lower respiratory tract infections.
Diao Z et al.·J Adv Res
2021Review
MotorPlex provides accurate variant detection across large muscle genes both in single myopathic patients and in pools of DNA samples.
Savarese M et al.·Acta Neuropathol Commun
2014Cohort
Metered-dose inhalers versus nebulization for the delivery of albuterol for acute exacerbations of wheezing or asthma in children: A systematic review with meta-analysis.
Payares-Salamanca L et al.·Pediatr Pulmonol
2020Meta-analysis
Congenital myopathies: pathophysiological mechanisms and promising therapies.
Zhang H et al.·J Transl Med
2024Review
[Congenital myopathies].
Cabello A et al.·Rev Neurol
2003Review
Top 10 resultsSearch PubMed ↗
Recent Gene-Specific Literature
Gene in title · MEDLINE · newest first
Europe PMC
Neurochemical and behavioral evidence of high abuse liability of 3F-NEB, a novel synthetic cathinone.
Pain S et al.·Eur J Pharmacol
2026
CRISPR Activation Reveals the Spliceogenicity of an Intronic NEB Variant in Fetuses With Arthrogryposis Multiplex Congenita 6.
Misceo D et al.·Clin Genet
2026🔓 Open Access
Effectiveness of Nebulized Bronchodilator - Enhanced Sputum Induction in Thai Patients with Presumed Pulmonary Tuberculosis; A Randomized Controlled Trial; (NeB-TB Trial).
Mingchay P et al.·Clin Infect Dis
2025Cohort
Efficacy and safety of tranexamic acid nebulization to control bleeding of hemoptysis: The TXA-NEB randomized controlled clinical trial.
Agrawal A et al.·Indian J Pharmacol
2025🔓 Open Access
Generation of a novel mouse model of nemaline myopathy due to recurrent NEB exon 55 deletion.
Coulson Z et al.·Skelet Muscle
2025🔓 Open AccessFunctional
Top 5 resultsSearch Europe PMC ↗

Clinical Trials

Active and recruiting trials from ClinicalTrials.gov

ClinicalTrials.gov
Inherited Non-Duchenne Myopathies

Clinical and Functional Assessment of Patients With Inherited Non-Duchenne Myopathies in Sohag University Hospital

RECRUITING
NCT06574919Sohag UniversityStarted 2024-08-01
Operable Breast Cancer

Randomized Controlled Trial to Assess Blockade of Voltage Gated Sodium Channels During Surgery in Operable Breast Cancer

ACTIVE NOT RECRUITING
NCT01916317Phase PHASE3Tata Memorial HospitalStarted 2011-12-12
0.5% lignocaine 60mM

External Resources

Links to major genomics databases and tools