CSTB
protein-codingcystatin B, the group of Cystatins, type 1
Gene summary
The cystatin superfamily encompasses proteins that contain multiple cystatin-like sequences. Some of the members are active cysteine protease inhibitors, while others have lost or perhaps never acquired this inhibitory activity. There are three inhibitory families in the superfamily, including the type 1 cystatins (stefins), type 2 cystatins and kininogens. This gene encodes a stefin that functions as an intracellular thiol protease inhibitor. The protein is able to form a dimer stabilized by noncovalent forces, inhibiting papain and cathepsins l, h and b. The protein is thought to play a role in protecting against the proteases leaking from lysosomes. Evidence indicates that mutations in this gene are responsible for the primary defects in patients with progressive myoclonic epilepsy (EPM1). One type of mutation responsible for EPM1 is the expansion in the promoter region of this gene of a CCCCGCCCCGCG repeat from 2-3 copies to 30-78 copies. [provided by RefSeq, Jul 2016]
- EPM1
- STFB
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~3.8 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0009698
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0009698
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0016619
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0009698
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0100062
Submitter: ClinGen
Variants in the CSTB gene have been reported in 4 affected individuals (from 2 families) with autosomal recessive (AR) developmental and epileptic encephalopathy since 2016 (Mancini et al.). Unlike Unverricht – Lundborg disease patients, all of 4 affected individuals do not have repeat expansion variants but have homozygous nonsense variant or homozygous frameshift variant, which is predicted to cause a loss of function of the protein. In summary, there is moderate evidence to support this gene-disease association. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel by 12/1/2020. As of 8/13/2024, this record underwent administrative updates to edit a typo in the evidence summary. No new evidence has been reviewed or added. Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability between three disease entities: (1) Unverricht – Lundborg syndrome(EPM1) (MONDO:0009698), and (2) developmental and epileptic encephalopathy (MONDO:0100062). Therefore, we have split curations for the disease entities, (1) Unverricht – Lundborg syndrome(EPM1) (MONDO:0009698), and (2) developmental and epileptic encephalopathy (MONDO:0100062).
Inheritance Pattern: AR
Disease ID:MONDO:0009698
Submitter: ClinGen
Variants in the CSTB gene have been reported in more than 55 affected individuals (from 40 families) with autosomal recessive (AR) Unverricht – Lundborg disease (aka EPM1 (Epilepsy, progressive myoclonic)) since 1996 (Pennacchio et al.). Most of affected individuals have repeat expansion variants, which is proved to cause a loss of function of the protein and it suggest homozygous loss of function is the mechanism of Unverricht – Lundborg disease for this gene. This gene-disease relationship is supported by expression study, and animal model study. In summary, CSTB is definitively associated with autosomal recessive Unverricht – Lundborg disease. This has been repeatedly demonstrated in both the research and clinical diagnostic setting, and has been upheld over time. This classification was approved by the ClinGen Epilepsy Gene Curation Expert Panel by 6/16/2020. Lumping and Splitting: Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability between three disease entities: (1) Unverricht – Lundborg syndrome(EPM1) (MONDO:0009698), and (2) developmental and epileptic encephalopathy (MONDO:0100062). Therefore, we have split curations for the disease entities, (1) Unverricht – Lundborg syndrome(EPM1) (MONDO:0009698), and (2) developmental and epileptic encephalopathy (MONDO:0100062).
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
Comments: Some medications (reports include valproate, N-acetylcysteine, levetiracetam) can result in marked improvement, but phenytoin can worsen neurologic manifestations, and can even increase cerebellar degeneration; Other medications (eg, carbamazepine, oxcarbazepine, tiagabine, vigabatrin, gabapentin, pregabalin) can worsen myoclonus/myoclonic seizures
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CSTB variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_000100.4. 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 | 1 | 31 | 34 | ||
| missense | 1 | 2 | 55 | 2 | 60 | |
| nonsense | 1 | 5 | 6 | |||
| start loss | 1 | 1 | ||||
| frameshift | 3 | 5 | 8 | |||
| splice donor/acceptor (+/-2bp) | 2 | 1 | 2 | 5 | ||
| Total | 7 | 16 | 58 | 33 | 0 | 114 |
Highest pathogenic variant AF is 0.0002983053
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_000091.1 | 3 | MANE Select | |
| Ensembl | ENSP00000291568.6 | 3 | MANE Select | |
| Ensembl | ENSP00000492123.1 | 2 | Standard | |
| Ensembl | ENSP00000492672.1 | 2 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Neutrophil degranulation
- Innate Immune System
- Immune System
- EGFR1
Biological Process
- adult locomotory behavior
- negative regulation of peptidase activity
- negative regulation of endopeptidase activity
- neutrophil degranulation
- negative regulation of proteolysis
Molecular Function
- protease binding
- RNA binding
- endopeptidase inhibitor activity
- cysteine-type endopeptidase inhibitor activity
Cellular Component
- extracellular region
- extracellular space
- nucleolus
- cytoplasm
- cytosol
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000291568
- Coding exons
- 3
- Length
- 3934
- Individuals with no LoFs
- 125699
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 42
- Defined
- 125741
- p
- 0.000167
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.0172 | 52 | 52.4 | 0.993 | 0.00000299 | 645 |
| Missense (PolyPhen) | 11 | 14.592 | 0.75384 | 206 | ||
| Synonymous | 0.577 | 21 | 24.6 | 0.852 | 0.00000182 | 175 |
| Loss of Function | 0.0148 | 3 | 3.03 | 0.991 | 1.30e-7 | 37 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0 | 0.0 | absent |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00033 | 0.00033 | rare |
| South Asian | 0 | 0.0 | absent |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: This is an intracellular thiol proteinase inhibitor. Tightly binding reversible inhibitor of cathepsins L, H and B.;
- Disease
- DISEASE: Epilepsy, progressive myoclonic 1 (EPM1) [MIM:254800]: An autosomal recessive disorder characterized by severe, stimulus- sensitive myoclonus and tonic-clonic seizures. The onset, occurring between 6 and 13 years of age, is characterized by convulsions. Myoclonus begins 1 to 5 years later. The twitchings occur predominantly in the proximal muscles of the extremities and are bilaterally symmetrical, although asynchronous. At first small, they become late in the clinical course so violent that the victim is thrown to the floor. Mental deterioration and eventually dementia develop. {ECO:0000269|PubMed:9012407}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.502
Intolerance Scores
- LoFtool
- 0.662
- RVIS EVS
- 0.26
- RVIS percentile EVS
- 69.83
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.691
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |