CEP57
protein-codingcentrosomal protein 57
Gene summary
This gene encodes a cytoplasmic protein called Translokin. This protein localizes to the centrosome and has a function in microtubular stabilization. The N-terminal half of this protein is required for its centrosome localization and for its multimerization, and the C-terminal half is required for nucleating, bundling and anchoring microtubules to the centrosomes. This protein specifically interacts with fibroblast growth factor 2 (FGF2), sorting nexin 6, Ran-binding protein M and the kinesins KIF3A and KIF3B, and thus mediates the nuclear translocation and mitogenic activity of the FGF2. It also interacts with cyclin D1 and controls nucleocytoplasmic distribution of the cyclin D1 in quiescent cells. This protein is crucial for maintaining correct chromosomal number during cell division. Mutations in this gene cause mosaic variegated aneuploidy syndrome, a rare autosomal recessive disorder. Multiple alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Aug 2011]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~42.7 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0013582
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0013582
Submitter: ClinGen
Centrosomal protein 57kDa, also known as Translokin or TLk, encoded by CEP57 gene functions in microtubular stabilization and mediates its nuclear translocation and mitogenic activity. Mutations in this gene have been found to cause mosaic variegated aneuploidy (MVA) syndrome type 2. Snape K et al., (2011) using exome sequencing identified biallelic LoF CEP57 mutation as a cause of constitutional mosaic aneuploidies. In this article, two Mexican siblings with MVA carry the same compound heterozygous CEP57 mutations, a 2-bp deletion (520delGA) in exon 5, and an 11-bp duplication in exon 9 (915_925dup11); Another 2 individuals with biallelic CEP57 mutations, homozygous for c.341C>T;p.R81X, and c.915_925dup11, from a cohort of 13 BUB1B negative families with MVA were also identified. De La Torre-Garcia et al., (2018) identified a Mexico boy with MVA homozygous for CEP57 c.915_925dup11. Pinson L et al., (2014) found a Morocan girl from a consanguineous family homozygous for CEP57 c.915_925dup11. Brightman DS et al.(2018) found a Pakistani girl with MVA of a consanguineous family homozygous for CEP57 c.697delA, p.Lys235Argfs*31). Experimental evidences showed CEP57 protein is localized to kinetochore contributing spindle microtubule organization, CEP57 depletion leads to missegregation of chromosome. siRNA resistant Cep57 wt with mutated siRNA targeted region in HeLa cells rescued the phenotypes. Research on CEP57 gene function in microtubule stability has been upheld over time. In summary, there have been sufficient evidences supporting the association of CEP57 with autosomal recessive inherited Mosaic Variegated Aneuploidy (MVA) type 2.
Inheritance Pattern: AR
Disease ID:MONDO:0013582
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0000141
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0013582
Submitter: Ambry Genetics
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Endocrine; Gastrointestinal; Musculoskeletal; Neurologic; Pulmonary
Intervention: Endocrine
Rationale: Individuals have been described as manifesting with hypothyroidism (among other features), and medical replacement therapy may be beneficial
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to CEP57 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_014679.5. 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 | 4 | 232 | 236 | |||
| missense | 1 | 611 | 24 | 1 | 637 | |
| nonsense | 6 | 1 | 3 | 10 | ||
| start loss | 1 | 1 | 2 | |||
| frameshift | 6 | 2 | 5 | 13 | ||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 1 | 5 | ||
| Total | 13 | 8 | 625 | 256 | 1 | 903 |
Highest pathogenic variant AF is 0.000037200905
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_055494.2 | 11 | MANE Select | |
| Ensembl | ENSP00000317902.5 | 11 | MANE Select | |
| RefSeq | NP_001230705.1 | 11 | Standard | |
| RefSeq | NP_001230706.1 | 10 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Regulation of PLK1 Activity at G2/M Transition
- Recruitment of mitotic centrosome proteins and complexes
- Loss of Nlp from mitotic centrosomes
- Loss of proteins required for interphase microtubule organization from the centrosome
- Centrosome maturation
Biological Process
- obsolete protein import into nucleus, translocation
- G2/M transition of mitotic cell cycle
- spermatid development
- fibroblast growth factor receptor signaling pathway
- regulation of G2/M transition of mitotic cell cycle
Molecular Function
- protein binding
- microtubule binding
- fibroblast growth factor binding
- protein homodimerization activity
- gamma-tubulin binding
Cellular Component
- nucleus
- Golgi apparatus
- centrosome
- cytosol
- microtubule
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000325542
- Coding exons
- 11
- Length
- 42729
- Individuals with no LoFs
- 125712
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 36
- Defined
- 125748
- p
- 0.000143
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -0.458 | 277 | 256 | 1.08 | 0.0000129 | 3296 |
| Missense (PolyPhen) | 113 | 110.8 | 1.0198 | 1501 | ||
| Synonymous | -0.929 | 102 | 90.7 | 1.12 | 0.00000454 | 888 |
| Loss of Function | 3.72 | 8 | 30.0 | 0.267 | 0.00000180 | 355 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.00043 | 0.00043 | rare |
| Ashkenazi Jewish | 0.00030 | 0.00030 | rare |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000097 | 0.000097 | rare |
| South Asian | 0.000065 | 0.000065 | rare |
| Other | 0.00033 | 0.00033 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Centrosomal protein which may be required for microtubule attachment to centrosomes. May act by forming ring- like structures around microtubules. Mediates nuclear translocation and mitogenic activity of the internalized growth factor FGF2, but that of FGF1. {ECO:0000269|PubMed:22321063}.;
- Disease
- DISEASE: Mosaic variegated aneuploidy syndrome 2 (MVA2) [MIM:614114]: A severe developmental disorder characterized by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple different chromosomes and tissues. Affected individuals typically present with severe intrauterine growth retardation and microcephaly. Eye anomalies, mild dysmorphism, variable developmental delay, and a broad spectrum of additional congenital abnormalities and medical conditions may also occur. The risk of malignancy is high, with rhabdomyosarcoma, Wilms tumor and leukemia reported in several cases. {ECO:0000269|PubMed:21552266}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.136
Intolerance Scores
- LoFtool
- 0.653
- RVIS EVS
- -0.05
- RVIS percentile EVS
- 50.34
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.515
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |