CHMP2B
protein-codingcharged multivesicular body protein 2B, the group of Charged multivesicular body proteins|ESCRT-III
Gene summary
This gene encodes a component of the heteromeric ESCRT-III complex (Endosomal Sorting Complex Required for Transport III) that functions in the recycling or degradation of cell surface receptors. ESCRT-III functions in the concentration and invagination of ubiquitinated endosomal cargos into intralumenal vesicles. The protein encoded by this gene is found as a monomer in the cytosol or as an oligomer in ESCRT-III complexes on endosomal membranes. It is expressed in neurons of all major regions of the brain. Mutations in this gene result in one form of familial frontotemporal lobar degeneration. [provided by RefSeq, Jul 2008]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~28.3 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0004976
Submitter: Orphanet
Inheritance Pattern: AD
Disease ID:MONDO:0010936
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0010936
Submitter: ClinGen
*CHMP2B* was first reported in relation to autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis 7 (FTD-ALS) in 2005 (Skibinski G, et al., 2005, PMID: 16041373). Dysfunctional endo-lysosomal and autophagic trafficking, leading to impaired proteostasis is common across the FTD-ALS spectrum. These pathways are, in part, mediated by CHMP2B, a protein that coordinates membrane scission events as a core component of the ESCRT machinery. Evidence supporting this gene-disease relationship includes case-level data and experimental data. At least 10 rare variants have been reported in relation to FTD-ALS (both truncating and missense variants). Variants in this gene have been reported in at least 13 probands in 10 publications (PMIDs: 16041373, 16807408, 17956895, 20352044, 23155438, 29411640, 29895397, 33770234, 23881933, 26777436), and segregated with disease in at least 10 additional family members in a Danish FTD pedigree (PMID: 16041373). The preponderance of evidence supporting a gene-disease relationship for *CHMP2B* relates to the CHMP2Bintron5 variant identified in the Danish FTD pedigree (PMID: 16041373), with a small number of variants also reported in ALS patients. Experimentally, this gene-disease relationship is supported by functional alteration, observed in both patient and transfected cells, causing an abnormal endosomal phenotype and neurodegeneration associated with the autophagy pathway (PMIDs: 22786763, 17683935) which could be rescued in patient cells by CRISPR/Cas-9 mediated correction of the variant (PMID: 28216144). Additionally, there are multiple mouse models recapitulating disease (PMIDs: 27329763, 34130995). In summary, *CHMP2B* is definitively associated with autosomal dominant frontotemporal dementia and/or amyotrophic lateral sclerosis 7. 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 ALS GCEP on 07/12/2022 (SOPv8).
Inheritance Pattern: AD
Disease ID:MONDO:0010936
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0010936
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0013861
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0010936
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Neurologic
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 CHMP2B variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_014043.4. 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 | 2 | 23 | 25 | |||
| missense | 2 | 3 | 71 | 6 | 82 | |
| nonsense | 1 | 7 | 2 | 10 | ||
| start loss | 1 | 1 | ||||
| frameshift | 5 | 5 | ||||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 4 | |||
| Total | 4 | 3 | 89 | 31 | 0 | 127 |
Highest pathogenic variant AF is 0.00010659554
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_054762.2 | 6 | MANE Select | |
| Ensembl | ENSP00000263780.4 | 6 | MANE Select | |
| RefSeq | NP_001231573.1 | 5 | Standard | |
| RefSeq | NP_001397706.1 | 7 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Endocytosis - Homo sapiens (human)
- Necroptosis - Homo sapiens (human)
- Disease
- Vesicle-mediated transport
- Membrane Trafficking
Biological Process
- autophagy
- nucleus organization
- endosome organization
- mitotic metaphase plate congression
- regulation of centrosome duplication
Molecular Function
- protein binding
- protein domain specific binding
- cadherin binding
Cellular Component
- ESCRT III complex
- cytoplasm
- lysosome
- endosome
- late endosome
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000263780
- Coding exons
- 6
- Length
- 28278
- Individuals with no LoFs
- 125656
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 92
- Defined
- 125748
- p
- 0.000366
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.339 | 103 | 113 | 0.910 | 0.00000571 | 1413 |
| Missense (PolyPhen) | 37 | 38.594 | 0.9587 | 532 | ||
| Synonymous | 0.144 | 34 | 35.1 | 0.969 | 0.00000177 | 375 |
| Loss of Function | 0.980 | 10 | 14.0 | 0.717 | 8.89e-7 | 145 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0.0053 | 0.0053 | notable |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00024 | 0.00024 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Probable core component of the endosomal sorting required for transport complex III (ESCRT-III) which is involved in multivesicular bodies (MVBs) formation and sorting of endosomal cargo proteins into MVBs. MVBs contain intraluminal vesicles (ILVs) that are generated by invagination and scission from the limiting membrane of the endosome and mostly are delivered to lysosomes enabling degradation of membrane proteins, such as stimulated growth factor receptors, lysosomal enzymes and lipids. The MVB pathway appears to require the sequential function of ESCRT-O, -I,-II and -III complexes. ESCRT-III proteins mostly dissociate from the invaginating membrane before the ILV is released. The ESCRT machinery also functions in topologically equivalent membrane fission events, such as the terminal stages of cytokinesis and the budding of enveloped viruses (HIV-1 and other lentiviruses). ESCRT-III proteins are believed to mediate the necessary vesicle extrusion and/or membrane fission activities, possibly in conjunction with the AAA ATPase VPS4.;
- Disease
- DISEASE: Frontotemporal dementia, chromosome 3-linked (FTD3) [MIM:600795]: Characterized by an onset of dementia in the late 50's initially characterized by behavioral and personality changes including apathy, restlessness, disinhibition and hyperorality, progressing to stereotyped behaviors, non-fluent aphasia, mutism and dystonia, with a marked lack of insight. The brains of individuals with FTD3 have no distinctive neuropathological features. They show global cortical and central atrophy, but no beta-amyloid deposits. {ECO:0000269|PubMed:16041373}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Amyotrophic lateral sclerosis 17 (ALS17) [MIM:614696]: An adult-onset progressive neurodegenerative disorder with predominantly lower motor neuron involvement, manifest as muscle weakness and wasting of the upper and lower limbs, bulbar signs, and respiratory insufficiency. {ECO:0000269|PubMed:16807408, ECO:0000269|PubMed:20352044}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.146
Intolerance Scores
- LoFtool
- 0.591
- RVIS EVS
- -0.16
- RVIS percentile EVS
- 41.64
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.922
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |