KNL1

protein-coding

kinetochore scaffold 1, the group of KNL1 complex|Protein phosphatase 1 regulatory subunits

Gene summary

The protein encoded by this gene is a component of the multiprotein assembly that is required for creation of kinetochore-microtubule attachments and chromosome segregation. The encoded protein functions as a scaffold for proteins that influence the spindle assembly checkpoint during the eukaryotic cell cycle and it interacts with at least five different kinetochore proteins and two checkpoint kinases. In adults, this gene is predominantly expressed in normal testes, various cancer cell lines and primary tumors from other tissues and is ubiquitously expressed in fetal tissues. This gene was originally identified as a fusion partner with the mixed-lineage leukemia (MLL) gene in t(11;15)(q23;q14). Mutations in this gene cause autosomal recessive primary microcephaly-4 (MCPH4). Alternative splicing results in multiple transcript variants encoding different isoforms. Additional splice variants have been described but their biological validity has not been confirmed. [provided by RefSeq, Jan 2013]

Previous symbols:

MCPH4
CASC5

MANE transcript

NM_144508.5

Inheritance

ClinVar variants

P:26U:181B:99

Top phenotype

Microcephaly 4, primary, autosomal recessive

gnomAD constraint

pLI —, LoF o/e 0.21

Max pathogenic AF

—

Genomic locus

chr15:40,594,020-40,664,342

External References & Databases

Ensembl (ENSG00000137812)

Transcript & Mutation Effects

hg38 • Region Span ~70.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

microcephaly 4, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011437

Submitter: G2P

microcephaly 4, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011437

Submitter: PanelApp Australia

microcephaly 4, primary, autosomal recessiveMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0011437

Submitter: Ambry Genetics

autosomal recessive primary microcephalySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016660

Submitter: Orphanet

microcephaly 4, primary, autosomal recessiveSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011437

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Microcephaly 4, primary, autosomal recessiveAR

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

Refs: 10521316; 22983954

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KNL1 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 201

Microcephaly 4, primary, autosomal recessiveTotal: 122

not specifiedTotal: 65

KNL1-related disorderTotal: 48

Inborn genetic diseasesTotal: 48

CASC5 & KNL1-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_144508.5. 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		1 clinvar	13 clinvar	65 clinvar	1 clinvar	80
missense	1 clinvar	3 clinvar	161 clinvar	31 clinvar	2 clinvar	198
nonsense	1 clinvar	3 clinvar	2 clinvar			6
start loss						0
frameshift	3 clinvar	11 clinvar	1 clinvar			15
splice donor/acceptor (+/-2bp)		3 clinvar	4 clinvar			7
Total	5	21	181	96	3	306

Highest pathogenic variant AF is 0.00014070922

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 14 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_144508.5	RefSeq	NP_653091.3	25	MANE Select
ENST00000399668.7	Ensembl	ENSP00000382576.3	25	MANE Select
NM_170589.5	RefSeq	NP_733468.3	26	Standard
ENST00000346991.10	Ensembl	ENSP00000335463.6	26	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

acrosome assembly
attachment of spindle microtubules to kinetochore
negative regulation of phosphatase activity
CENP-A containing nucleosome assembly
protein localization to kinetochore

Molecular Function

protein binding

Cellular Component

condensed chromosome kinetochore
acrosomal vesicle
nucleus
nucleoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000346991
Coding exons: 26
Length: 70323
Individuals with no LoFs: 124692
Homozygous LoFs: 0
Heterozygous LoFs: 97
Defined: 124789
p: 0.000389

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.00813	1166	1.17e+3	1.00	0.0000556	15723
Missense (PolyPhen)		204	237.4	0.8593		3613
Synonymous	0.439	396	407	0.972	0.0000203	4175
Loss of Function	6.86	19	88.8	0.214	0.00000436	1262

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00013	rare
Latino/Admixed American	0.00015	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000058	0.000056	rare
Finnish	0.00074	0.00074	rare
European (Non-Finnish)	0.00060	0.00060	rare
South Asian	0.000033	0.000033	rare
Other	0.00067	0.00066	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Performs two crucial functions during mitosis: it is essential for spindle-assembly checkpoint signaling and for correct chromosome alignment. Required for attachment of the kinetochores to the spindle microtubules. Directly links BUB1 and BUB1B to kinetochores. Part of the MIS12 complex, which may be fundamental for kinetochore formation and proper chromosome segregation during mitosis. Acts in coordination with CENPK to recruit the NDC80 complex to the outer kinetochore. {ECO:0000269|PubMed:15502821, ECO:0000269|PubMed:17981135, ECO:0000269|PubMed:18045986}.;
Disease: DISEASE: Microcephaly 4, primary, autosomal recessive (MCPH4) [MIM:604321]: 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. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Affected individuals are mentally retarded. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits due to degenerative brain disorder. {ECO:0000269|PubMed:22983954, ECO:0000269|PubMed:26626498}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.102

Intolerance Scores

RVIS EVS: 1.65
RVIS percentile EVS: 96.19

Essentials

Essential (gene trap): E