INCENP

protein-coding

inner centromere protein, the group of Chromosomal passenger complex

Gene summary

In mammalian cells, 2 broad groups of centromere-interacting proteins have been described: constitutively binding centromere proteins and 'passenger,' or transiently interacting, proteins (reviewed by Choo, 1997). The constitutive proteins include CENPA (centromere protein A; MIM 117139), CENPB (MIM 117140), CENPC1 (MIM 117141), and CENPD (MIM 117142). The term 'passenger proteins' encompasses a broad collection of proteins that localize to the centromere during specific stages of the cell cycle (Earnshaw and Mackay, 1994 [PubMed 8088460]). These include CENPE (MIM 117143); MCAK (MIM 604538); KID (MIM 603213); cytoplasmic dynein (e.g., MIM 600112); CliPs (e.g., MIM 179838); and CENPF/mitosin (MIM 600236). The inner centromere proteins (INCENPs) (Earnshaw and Cooke, 1991 [PubMed 1860899]), the initial members of the passenger protein group, display a broad localization along chromosomes in the early stages of mitosis but gradually become concentrated at centromeres as the cell cycle progresses into mid-metaphase. During telophase, the proteins are located within the midbody in the intercellular bridge, where they are discarded after cytokinesis (Cutts et al., 1999 [PubMed 10369859]).[supplied by OMIM, Mar 2008]

MANE transcript

NM_001040694.2

Inheritance

—

ClinVar variants

P:1U:200B:24

Top phenotype

Nephronophthisis

gnomAD constraint

pLI —, LoF o/e 0.19

Max pathogenic AF

—

Genomic locus

chr11:62,123,998-62,155,474

External References & Databases

Ensembl (ENSG00000149503)

Transcript & Mutation Effects

hg38 • Region Span ~31.5 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to INCENP variants in ClinVar

3 Conditions Cataloged

not specifiedTotal: 200

not providedTotal: 31

NephronophthisisTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001040694.2. 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	4 clinvar	4 clinvar	9
missense		1 clinvar	194 clinvar	11 clinvar	5 clinvar	211
nonsense						0
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)			5 clinvar			5
Total	0	1	200	15	9	225

Highest pathogenic variant AF is 0.0029956666

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 24 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001040694.2	RefSeq	NP_001035784.1	18	MANE Select
ENST00000394818.8	Ensembl	ENSP00000378295.3	18	MANE Select
NM_020238.3	RefSeq	NP_064623.2	17	Standard
ENST00000278849.4	Ensembl	ENSP00000278849.4	17	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signal Transduction
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal
Amplification of signal from the kinetochores
Mitotic Spindle Checkpoint
Cell Cycle Checkpoints

Biological Process

mitotic sister chromatid segregation
mitotic cytokinesis
chromosome segregation
regulation of mitotic cytokinesis

Molecular Function

protein binding

Cellular Component

chromosome, centromeric region
kinetochore
condensed chromosome kinetochore
lateral element
central element

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394818
Coding exons: 18
Length: 29191
Individuals with no LoFs: 125714
Homozygous LoFs: 0
Heterozygous LoFs: 33
Defined: 125747
p: 0.000131

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.766	545	598	0.912	0.0000437	5931
Missense (PolyPhen)		29	52.112	0.55649		561
Synonymous	0.0863	233	235	0.993	0.0000153	1826
Loss of Function	5.11	9	46.7	0.193	0.00000244	530

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.000062	rare
Latino/Admixed American	0.00044	0.00040	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000056	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00012	0.00012	rare
South Asian	0.000066	0.000065	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Acts as a scaffold regulating CPC localization and activity. The C-terminus associates with AURKB or AURKC, the N-terminus associated with BIRC5/survivin and CDCA8/borealin tethers the CPC to the inner centromere, and the microtubule binding activity within the central SAH domain directs AURKB/C toward substrates near microtubules (PubMed:15316025, PubMed:12925766, PubMed:27332895). The flexibility of the SAH domain is proposed to allow AURKB/C to follow substrates on dynamic microtubules while ensuring CPC docking to static chromatin (By similarity). Activates AURKB and AURKC (PubMed:27332895). Required for localization of CBX5 to mitotic centromeres (PubMed:21346195). Controls the kinetochore localization of BUB1 (PubMed:16760428). {ECO:0000250|UniProtKB:P53352, ECO:0000269|PubMed:12925766, ECO:0000269|PubMed:15316025, ECO:0000269|PubMed:16760428, ECO:0000269|PubMed:21346195, ECO:0000269|PubMed:27332895}.;

Recessive Scores

pRec: 0.127

Intolerance Scores

LoFtool: 0.413
RVIS EVS: 0.83
RVIS percentile EVS: 88.13

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.849

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High