CENPE

protein-coding

centromere protein E, the group of Kinesins|Protein phosphatase 1 regulatory subunits

Gene summary

Centrosome-associated protein E (CENPE) is a kinesin-like motor protein that accumulates in the G2 phase of the cell cycle. Unlike other centrosome-associated proteins, it is not present during interphase and first appears at the centromere region of chromosomes during prometaphase. This protein is required for stable spindle microtubule capture at kinetochores which is a necessary step in chromosome alignment during prometaphase. This protein also couples chromosome position to microtubule depolymerizing activity. Alternative splicing results in multiple transcript variants encoding distinct protein isoforms. [provided by RefSeq, Nov 2014]

MANE transcript

NM_001813.3

Inheritance

ClinVar variants

P:7U:318B:133

Top phenotype

Microcephaly 13, primary, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.23

Max pathogenic AF

—

Genomic locus

chr4:103,105,349-103,198,445

External References & Databases

Ensembl (ENSG00000138778)

Transcript & Mutation Effects

hg38 • Region Span ~93.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly 13, primary, autosomal recessiveLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0014473

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive primary microcephalyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: ClinGen

CENPE was first reported in relation to Microcephaly 13, primary, autosomal recessive in 2014 (Mirzaa et al., PMID: 24748105). This disease is characterized by microcephalic primordial dwarfism associated with developmental delay, simplified gyri and other isolated abnormalities. At least 2 missense variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in CENPE have been reported in individuals with the following disease entities: Microcephaly 13, primary, autosomal recessive (OMIM:616051). CENPE is also associated with Seckel syndrome (ORPHA:808) in orphanet. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism and inheritance pattern and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity: Microcephaly 13, primary, autosomal recessive (OMIM:616051). This gene-disease relationship is supported by a cenpe conditional knockout (KO) mouse model. KO mice fibroblast show mitotic chromosomal misalignment comparable to patient-derived LCLs (PMID: 12361599). In addition, embryonic tissue from CENP-meta KO fruit flies show disrupted mitosis and misaligned chromosomes (PMID: 10893249).Variants in this gene have been reported in at least 1 proband in 1 publication (PMID: 24748105). Variants in this gene segregated with disease in 1 additional family member. In summary, there is limited evidence to support this gene-disease relationship. Although more evidence is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. This classification was approved by the ClinGen brain malformations expert panel on 11/28/2023 (SOP Version 10 November 2023).

microcephaly 13, primary, autosomal recessiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014473

Submitter: Ambry Genetics

microcephaly 13, primary, autosomal recessiveLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014473

Submitter: Illumina

Seckel syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019342

Submitter: Orphanet

autosomal recessive primary microcephalyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: LiferaOmics

ClinGen Primary autosomal recessive microcephaly (MCPH13) Classification: LIMITED (ClinGen approved 12/05/2023) Official ClinGen scoring: Genetic evidence = 1.0 / 12 (based on PMID:24748105) Experimental evidence = 1.0 / 6 Total = 2.0 - Limited Genetic evidence – Current case: One proband, positive parental consanguinity; homozygous predicted loss-of-function; AR inheritance; no additional genotyped affected relatives; no segregation or case-control data. Case-level points (default for predicted null in AR disease) = 1.0 (AR predicted/proven null = 1.5, −0.5 downgrade for homozygosity/consanguinity); segregation = 0; case-control = 0. Our case contribution = 1.0 / 12 Updated genetic evidence total (published + our) = 2.0 / 12 Experimental evidence – Published (ClinGen curated baseline): Functional cellular evidence of mitotic defects and biological role in kinetochore-microtubule attachment scored by ClinGen = 1.0 / 6 Experimental evidence total remains = 1.0 / 6 Overall score = 3.0

Clinical Genomic Database (CGD)

Microcephaly 13, primary, autosomal recessiveAR

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

Refs: 24748105

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CENPE variants in ClinVar

6 Conditions Cataloged

not specifiedTotal: 348

not providedTotal: 220

CENPE-related disorderTotal: 46

Microcephaly 13, primary, autosomal recessiveTotal: 20

AutismTotal: 1

See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001813.3. 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			1 clinvar	81 clinvar	1 clinvar	83
missense	1 clinvar	2 clinvar	305 clinvar	46 clinvar	5 clinvar	359
nonsense		1 clinvar	3 clinvar			4
start loss						0
frameshift		2 clinvar	2 clinvar			4
splice donor/acceptor (+/-2bp)		1 clinvar	7 clinvar			8
Total	1	6	318	127	6	458

Highest pathogenic variant AF is 0.00019037769

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 38 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001813.3	RefSeq	NP_001804.2	49	MANE Select
ENST00000265148.9	Ensembl	ENSP00000265148.3	49	MANE Select
NM_001286734.2	RefSeq	NP_001273663.1	47	Standard
ENST00000380026.8	Ensembl	ENSP00000369365.3	47	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Regulation of sister chromatid separation at the metaphase-anaphase transition
Signal Transduction
Vesicle-mediated transport
Membrane Trafficking
Kinesins

Biological Process

mitotic cell cycle
retrograde vesicle-mediated transport, Golgi to endoplasmic reticulum
microtubule-based movement
mitotic spindle organization
chromosome segregation

Molecular Function

microtubule motor activity
protein binding
ATP binding
microtubule binding
ATPase activity

Cellular Component

chromosome, centromeric region
kinetochore
condensed chromosome kinetochore
condensed chromosome, centromeric region
nucleus

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000265148
Coding exons: 49
Length: 92604
Individuals with no LoFs: 125642
Homozygous LoFs: 0
Heterozygous LoFs: 96
Defined: 125738
p: 0.000382

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.27	1113	1.24e+3	0.899	0.0000588	18071
Missense (PolyPhen)		204	324.56	0.62853		4867
Synonymous	-0.643	438	421	1.04	0.0000199	4540
Loss of Function	8.44	32	140	0.229	0.00000689	1972

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00044	0.00038	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00034	0.00032	rare
South Asian	0.0015	0.0012	notable
Other	0.00036	0.00033	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Microtubule plus-end-directed kinetochore motor which plays an important role in chromosome congression, microtubule- kinetochore conjugation and spindle assembly checkpoint activation. Drives chromosome congression (alignment of chromosomes at the spindle equator resulting in the formation of the metaphase plate) by mediating the lateral sliding of polar chromosomes along spindle microtubules towards the spindle equator and by aiding the establishment and maintenance of connections between kinetochores and spindle microtubules (PubMed:7889940, PubMed:23891108, PubMed:25395579). The transport of pole-proximal chromosomes towards the spindle equator is favored by microtubule tracks that are detyrosinated (PubMed:25908662). Acts as a processive bi-directional tracker of dynamic microtubule tips; after chromosomes have congressed, continues to play an active role at kinetochores, enhancing their links with dynamic microtubule ends (PubMed:23955301). Suppresses chromosome congression in NDC80-depleted cells and contributes positively to congression only when microtubules are stabilized (PubMed:25743205). Plays an important role in the formation of stable attachments between kinetochores and spindle microtubules (PubMed:17535814) The stabilization of kinetochore-microtubule attachment also requires CENPE-dependent localization of other proteins to the kinetochore including BUB1B, MAD1 and MAD2. Plays a role in spindle assembly checkpoint activation (SAC) via its interaction with BUB1B resulting in the activation of its kinase activity, which is important for activating SAC. Necessary for the mitotic checkpoint signal at individual kinetochores to prevent aneuploidy due to single chromosome loss (By similarity). {ECO:0000250|UniProtKB:Q6RT24, ECO:0000269|PubMed:17535814, ECO:0000269|PubMed:23891108, ECO:0000269|PubMed:23955301, ECO:0000269|PubMed:25395579, ECO:0000269|PubMed:25743205, ECO:0000269|PubMed:25908662, ECO:0000269|PubMed:7889940}.;
Disease: DISEASE: Microcephaly 13, primary, autosomal recessive (MCPH13) [MIM:616051]: A form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age- related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. {ECO:0000269|PubMed:24748105}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.801
RVIS EVS: -0.55
RVIS percentile EVS: 19.97

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Indispensability pred.: E
Indispensability score: 0.835

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium