PCNT
protein-codingpericentrin
Gene summary
The protein encoded by this gene binds to calmodulin and is expressed in the centrosome. It is an integral component of the pericentriolar material (PCM). The protein contains a series of coiled-coil domains and a highly conserved PCM targeting motif called the PACT domain near its C-terminus. The protein interacts with the microtubule nucleation component gamma-tubulin and is likely important to normal functioning of the centrosomes, cytoskeleton, and cell-cycle progression. Mutations in this gene cause Seckel syndrome-4 and microcephalic osteodysplastic primordial dwarfism type II. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]
- PCNT2
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~121.6 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0008872
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0008872
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0008872
Submitter: Ambry Genetics
Inheritance Pattern: AR
Disease ID:MONDO:0008872
Submitter: G2P
Inheritance Pattern: AR
Disease ID:MONDO:0016820
Submitter: Genomics England PanelApp
Inheritance Pattern: AR
Disease ID:MONDO:0008872
Submitter: ClinGen
PCNT was first reported in relation to autosomal recessive microcephalic osteodysplastic primordial dwarfism, type II (MOPDII) in 2008 (Rauch et al., PMID: 18174396 and Griffith et al., PMID: 18157127). Microcephalic osteodysplastic primordial dwarfism type II is characterized by intrauterine growth retardation (IUGR), severe proportionate short stature, and microcephaly. Patients occasionally present with additional syndromic features, including heart defects (PMID: 29961235) and oligodontia (PMID: 31606423) in addition to the typical skeletal manifestations observed. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, microcephalic osteodysplastic primordial dwarfism, type II (OMIM:210720) and Seckel syndrome. Seven variants (nonsense, frameshift, and canonical splice site) that have been reported in five probands in four publications (PMIDs: 18174396, 26231886, 33460028, 35568357) are included in this curation meeting phenotypic criteria including IUGR, short stature, and microcephaly. More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is reported to be loss of function. The curation for this gene-disease relationship did not include experimental evidence. In summary, there is definitive evidence supporting the relationship between PCNT and autosomal recessive microcephalic osteodysplastic primordial dwarfism, type II. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date July 21, 2023 (SOP Version 9) and reviewed by experts from the ClinGen Syndromic Disorders GCEP on August 27, 2024 (SOP Version 10).
Inheritance Pattern: AR
Disease ID:MONDO:0008872
Submitter: Labcorp Genetics (formerly Invitae)
Clinical Genomic Database (CGD)
Manifestation: Craniofacial; Musculoskeletal; 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: Individuals may have cerebral neurovascular anomalies
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to PCNT variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_006031.6. 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 | 20 | 1267 | 7 | 1294 | ||
| missense | 1 | 2 | 1594 | 201 | 12 | 1810 |
| nonsense | 90 | 63 | 8 | 161 | ||
| start loss | 0 | |||||
| frameshift | 103 | 75 | 4 | 182 | ||
| splice donor/acceptor (+/-2bp) | 9 | 59 | 9 | 4 | 81 | |
| Total | 203 | 199 | 1635 | 1472 | 19 | 3528 |
Highest pathogenic variant AF is 0.00011023794
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_006022.3 | 47 | MANE Select | |
| Ensembl | ENSP00000352572.5 | 47 | MANE Select | |
| RefSeq | NP_001302458.1 | 45 | Standard | |
| Ensembl | ENSP00000404708.2 | 13 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Olfactory bulb development and olfactory learning
- 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
Biological Process
- G2/M transition of mitotic cell cycle
- microtubule cytoskeleton organization
- mitotic spindle organization
- signal transduction
- regulation of G2/M transition of mitotic cell cycle
Molecular Function
- protein binding
- calmodulin binding
- protein-containing complex scaffold activity
Cellular Component
- centrosome
- centriole
- microtubule organizing center
- cytosol
- microtubule
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000359568
- Coding exons
- 47
- Length
- 121647
- Individuals with no LoFs
- 125383
- Homozygous LoFs
- 1
- Heterozygous LoFs
- 364
- Defined
- 125748
- p
- 0.00145
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | -1.73 | 2093 | 1.88e+3 | 1.11 | 0.000129 | 21658 |
| Missense (PolyPhen) | 172 | 179.54 | 0.95802 | 2051 | ||
| Synonymous | -4.52 | 975 | 811 | 1.20 | 0.0000589 | 6485 |
| Loss of Function | 3.53 | 117 | 166 | 0.705 | 0.00000901 | 1901 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.0014 | 0.0014 | notable |
| Latino/Admixed American | 0.0014 | 0.0014 | notable |
| Ashkenazi Jewish | 0.0070 | 0.0037 | notable |
| East Asian | 0.00054 | 0.00054 | rare |
| Finnish | 0.00020 | 0.00018 | rare |
| European (Non-Finnish) | 0.0014 | 0.0013 | notable |
| South Asian | 0.0028 | 0.0028 | notable |
| Other | 0.0020 | 0.0018 | notable |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Integral component of the filamentous matrix of the centrosome involved in the initial establishment of organized microtubule arrays in both mitosis and meiosis. Plays a role, together with DISC1, in the microtubule network formation. Is an integral component of the pericentriolar material (PCM). May play an important role in preventing premature centrosome splitting during interphase by inhibiting NEK2 kinase activity at the centrosome. {ECO:0000269|PubMed:10823944, ECO:0000269|PubMed:11171385, ECO:0000269|PubMed:18955030, ECO:0000269|PubMed:20599736}.;
- Disease
- DISEASE: Microcephalic osteodysplastic primordial dwarfism 2 (MOPD2) [MIM:210720]: Adults with this rare inherited condition have an average height of 100 centimeters and a brain size comparable to that of a 3-month-old baby, but are of near-normal intelligence. {ECO:0000269|PubMed:18157127, ECO:0000269|PubMed:18174396}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.214
Intolerance Scores
- LoFtool
- 0.898
- RVIS EVS
- 3.57
- RVIS percentile EVS
- 99.52
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- S
- Essential (gene trap)
- E
- Indispensability pred.
- E
- Indispensability score
- 0.898
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | High | High | High |
| Primary Immunodeficiency | High | High | High |
| Cancer | High | High | High |