CLPB
protein-codingClpB family mitochondrial disaggregase, the group of Chaperonins|AAA ATPases|Ankyrin repeat domain containing
Gene summary
This gene belongs to the ATP-ases associated with diverse cellular activities (AAA+) superfamily. Members of this superfamily form ring-shaped homo-hexamers and have highly conserved ATPase domains that are involved in various processes including DNA replication, protein degradation and reactivation of misfolded proteins. All members of this family hydrolyze ATP through their AAA+ domains and use the energy generated through ATP hydrolysis to exert mechanical force on their substrates. In addition to an AAA+ domain, the protein encoded by this gene contains a C-terminal D2 domain, which is characteristic of the AAA+ subfamily of Caseinolytic peptidases to which this protein belongs. It cooperates with Hsp70 in the disaggregation of protein aggregates. Allelic variants of this gene are associated with 3-methylglutaconic aciduria, which causes cataracts and neutropenia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~149.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0030726
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014561
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0014561
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0014561
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0014561
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0009723
Submitter: ClinGen
The relationship between CLPB and Leigh syndrome spectrum was evaluated using the ClinGen Clinical Validity Framework as of June 8, 2020. The CLPB gene has a function in mitochondrial protein disaggregation, but the disease mechanism is currently somewhat unclear. The CLPB gene was first reported in relation to autosomal recessive Leigh syndrome spectrum in 2015 (PMIDs: 25597511, 25597510). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Many other cases have been reported with CLPB-related disease, however brain imaging was not performed or was not consistent with Leigh syndrome spectrum. 3-methylglutaconic aciduria is a common finding in individuals with CLPB-related disease. This curation included three unique variants identified in three unrelated cases from two publications (PMIDs: 25597511, 25597510). No segregation data were available. Loss of function is implicated as the mechanism of disease. This gene-disease association is also supported by animal models (PMIDs: 25597510, 25650066). In summary, there is limited evidence to support this gene-disease relationship. While more evidence is needed to establish this relationship definitively, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the NICHD U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel June 8, 2020 (SOP Version 7).
Clinical Genomic Database (CGD)
Manifestation: Allergy/Immunology/Infectious; Biochemical; Cardiovascular; Endocrine; Hematologic; Neurologic; Oncologic; Ophthalmologic
Intervention: Allergy/Immunology/Infectious; Oncologic
Rationale: 3-methylglutaconic aciduria can involve neutropenia, with recurrent/severe infections in some, and awareness may allow early and aggressive management of infections; Indidivuals with 3-methylglutaconic aciduria, type VIIB have been reported with leukemia, and awareness may allow early diagnosis and management; HSCT has been described in 3-methylglutaconic aciduria, type VIIA; Neutropenia, severe congenital, 9 may involve many of the features of 3-methylglutaconic aciduria, including increased risk of infections and certain types of cancer, and awareness may allow early diagnosis and management
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CLPB variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001258392.3. 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 | 6 | 158 | 1 | 165 | ||
| missense | 9 | 15 | 405 | 25 | 1 | 455 |
| nonsense | 9 | 5 | 2 | 16 | ||
| start loss | 1 | 1 | ||||
| frameshift | 9 | 2 | 2 | 13 | ||
| splice donor/acceptor (+/-2bp) | 10 | 3 | 13 | |||
| Total | 27 | 32 | 419 | 183 | 2 | 663 |
Highest pathogenic variant AF is 0.00019764512
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001245321.1 | 16 | MANE Select | |
| Ensembl | ENSP00000441518.1 | 16 | MANE Select | |
| RefSeq | NP_001245322.1 | 15 | Standard | |
| RefSeq | NP_001245323.1 | 18 | Standard |
Model Organisms & Knockout Phenotypes
Observed phenotypic effects in mouse and zebrafish models
| Gene / Model | Organism | Observed Phenotype |
|---|---|---|
| clpb | Danio rerio | Structure: glycinergic neuron Quality: decreased amount abnormal |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Longevity regulating pathway - multiple species - Homo sapiens (human)
Biological Process
- cellular response to heat
Molecular Function
- molecular_function
- protein binding
- ATP binding
- ATPase activity
Cellular Component
- cellular_component
- mitochondrion
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000294053
- Coding exons
- 17
- Length
- 142224
- Individuals with no LoFs
- 125631
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 117
- Defined
- 125748
- p
- 0.000465
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.05 | 378 | 440 | 0.859 | 0.0000261 | 4588 |
| Missense (PolyPhen) | 91 | 154.87 | 0.58759 | 1619 | ||
| Synonymous | 1.21 | 156 | 176 | 0.885 | 0.0000103 | 1440 |
| Loss of Function | 3.81 | 13 | 38.5 | 0.337 | 0.00000207 | 412 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00037 | 0.00037 | rare |
| Latino/Admixed American | 0.00035 | 0.00035 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.0040 | 0.0040 | notable |
| Finnish | 0.00028 | 0.00028 | rare |
| European (Non-Finnish) | 0.00011 | 0.00011 | rare |
| South Asian | 0.00016 | 0.00016 | rare |
| Other | 0.00049 | 0.00049 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: May function as a regulatory ATPase and be related to secretion/protein trafficking process.;
Recessive Scores
- pRec
- 0.186
Intolerance Scores
- LoFtool
- 0.804
- RVIS EVS
- 0.25
- RVIS percentile EVS
- 69.62
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- N
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.950
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |