CHMP2B

Chr 3AD

charged multivesicular body protein 2B

Also known as: ALS17, CHMP2.5, DMT1, FTDALS7, VPS2-2, VPS2B

NCBI Gene: 25978 ENSG00000083937 UniProt: Q9UQN3 OMIM: 609512

The protein is a core component of the ESCRT-III complex that sorts endosomal cargo proteins into multivesicular bodies for lysosomal degradation and functions in membrane fission events including cytokinesis. Mutations cause frontotemporal dementia and/or amyotrophic lateral sclerosis 7, typically presenting in adulthood with progressive cognitive decline and/or motor neuron degeneration. Inheritance is autosomal dominant.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

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]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 1.221 OMIM phenotype

Clinical Summary— CHMP2B

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Gene-Disease Validity (ClinGen)

frontotemporal dementia and/or amyotrophic lateral sclerosis 7 · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Low constraint (pLI 0.00) — loss-of-function variants are relatively tolerated in the population.

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ClinVar Variants

6 unique Pathogenic / Likely Pathogenic· 110 VUS of 196 total submissions

Explore recent and relevant literature in Research Assistant →

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GeneReview available — CHMP2B

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Tolerant — LoF & missense variants common in population

LoF Constraint?

1.22LOEUF

pLI 0.000

Z-score 0.98

OE 0.72 (0.44–1.22)

Tolerant

Highly tolerant — LoF variants common in population

Missense Constraint?

0.34Z-score

OE missense 0.91 (0.78–1.07)

103 obs / 113.2 exp

Tolerant

Mild missense constraint

Observed / Expected Ratios?

LoF OE?0.72 (0.44–1.22)

0≤0.351.4

Missense OE?0.91 (0.78–1.07)

0≤0.61.4

Synonymous OE?0.97

0≤1.21.6

LoF obs/exp: 10 / 14.0Missense obs/exp: 103 / 113.2Syn Z: 0.14

This gene — mechanism propensity

0.87top 5%

GOF

0.7030th %ile

LOF

0.2288th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative and gain-of-function). Both the Badonyi & Marsh prediction and the broader genomic evidence point to dominant-negative as the predominant mechanism. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median · 1 literature citation

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNDepletion of endogenous CHMP2B by RNAi resulted in morphological changes similar to those induced by mutant CHMP2B, consistent with dominant-negative activity of pathogenic mutants.1

GOFChromosome 3-linked frontotemporal dementia (FTD3) is caused by a gain-of-function mutation in CHMP2B, resulting in the production of a truncated toxic protein, CHMP2BIntron5.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312.

References

ClinVar Variant Classifications

196 submitted variants in ClinVar

ClinVar

Classification Summary

Pathogenic4

Likely Pathogenic2

VUS110

Likely Benign48

Benign18

Conflicting5

Pathogenic

Likely Pathogenic

110

VUS

Likely Benign

Benign

Conflicting

Curated Variants Distribution

Classified variants from ClinVar · 5 ACMG categories

Classification	LoF	Missense + Inframe	Non-coding	Synonymous	Total
Pathogenic	2	2	0	0	4
Likely Pathogenic	0	2	0	0	2
VUS	13	72	24	1	110
Likely Benign	1	3	24	20	48
Benign	0	0	14	4	18
Conflicting	—				5
Total	16	79	62	25	187

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

View in ClinVar →

8 pathogenic / likely-pathogenic (of 22) ClinVar copy-number / structural variants overlap CHMP2B — these span large chromosomal regions, not the gene specifically, and are excluded from the counts above. Explore in CNV tools →