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…

Primary Disease Associations & Inheritance

Frontotemporal dementia and/or amyotrophic lateral sclerosis 7MIM #600795

Clinical highlights

Gene–disease validity (ClinGen)

Definitive · frontotemporal dementia and/or amyotrophic lateral sclerosis 7 · AD · ClinGen 2022

Active trials

Pubs (1 yr)

—

P/LP submissions

—

P/LP missense

1.22

LOEUF

Multiple*

Mechanism· predicted

📖

GeneReview available — CHMP2B

Authoritative clinical overview · Recommended first read

Open GeneReview ↗

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

Background carrier burden — how many people carry a rare variant somewhere in CHMP2B?

gnomAD v4 · ~731k individuals · PASS only

Rare means allele frequency under

Rare missense

1 in 170

296 rare PASS variants

Rare truncating (LoF)

1 in 660

70 rare PASS variants

Rare synonymous (reference)

1 in 560

92 rare PASS variants

Rare missense and truncating variants are carried at similar rates in CHMP2B; this gene does not show strong loss-of-function constraint by this measure. A background rate for each class, not the frequency of any particular variant; thin-coverage exons undercount.

By genetic ancestry · 9 gnomAD groups · rare = under 0.1% in that group

Group	People	Missense	Truncating
European (non-Finnish)	~556k	1 in 280	1 in 1,800
South Asian	~43k	1 in 270	1 in 1,200
Remaining (unassigned)	~30k	1 in 140	1 in 430
European (Finnish)	~27k	1 in 560	≈ 1 in 27,000
Admixed American	~22k	1 in 190	1 in 2,400
African / African American	~21k	1 in 120	1 in 460
East Asian	~20k	1 in 130	1 in 1,700
Ashkenazi Jewish	~13k	1 in 1,400	none seen
Middle Eastern	~2,884	1 in 210	≈ 1 in 960

Each group is summed over the variants that are rare in that group. Grey ≈ figures rest on fewer than five expected carriers — too few to distinguish groups. Differences mostly reflect how many people were sampled and how much variation each ancestry carries, not disease risk.

Exome coverage (gnomAD): 4 of 6 coding exons well covered in gnomAD exomes; exons 4, 5 marginal. Genomes: all 6.? see exons ↓