KNL1

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

Basic information

Region (hg38): 15:40594019-40664342

Previous symbols: [ "MCPH4", "CASC5" ]

Links

ENSG00000137812 ∙ NCBI:57082 ∙ OMIM:609173 ∙ HGNC:24054 ∙ Uniprot:Q8NG31 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• microcephaly 4, primary, autosomal recessive (Moderate), mode of inheritance: AR
• microcephaly 4, primary, autosomal recessive (Strong), mode of inheritance: AR
• autosomal recessive primary microcephaly (Supportive), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Microcephaly 4, primary, autosomal recessive	AR	General	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	Neurologic	10521316; 22983954

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the KNL1 gene.

• not provided (223 variants)
• Microcephaly 4, primary, autosomal recessive (135 variants)
• not specified (59 variants)
• Inborn genetic diseases (43 variants)
• Primary Microcephaly, Recessive (18 variants)
• KNL1-related condition (4 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the KNL1 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous		1	14	29	5	49
missense	1	2	132	13	10	158
nonsense	1	1	1			3
start loss			1			1
frameshift	3	9	1			13
inframe indel			4			4
splice donor/acceptor (+/-2bp)		1	1			2
splice region			5	8		13
non coding			12	47	36	95
Total	5	14	166	89	51

Highest pathogenic variant AF is 0.0000132

Variants in KNL1

This is a list of pathogenic ClinVar variants found in the KNL1 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
15-40594267-G-A		Microcephaly 4, primary, autosomal recessive	Uncertain significance (Jan 13, 2018)
15-40594310-C-G		Microcephaly 4, primary, autosomal recessive	Uncertain significance (Mar 23, 2018)
15-40594355-G-A		Primary Microcephaly, Recessive	Likely benign (Jun 14, 2016)
15-40602637-C-A			Benign (Jul 07, 2018)
15-40602862-G-T			Likely benign (Sep 22, 2018)
15-40602900-G-A		Microcephaly 4, primary, autosomal recessive	Uncertain significance (Jan 13, 2018)
15-40602919-G-T		Microcephaly 4, primary, autosomal recessive	Uncertain significance (Mar 30, 2018)
15-40602927-CAAA-C			Uncertain significance (May 01, 2013)
15-40602941-G-T		Microcephaly 4, primary, autosomal recessive	Uncertain significance (Apr 27, 2017)
15-40602952-G-A		Microcephaly 4, primary, autosomal recessive	Uncertain significance (Feb 16, 2018)
15-40603101-A-T			Likely benign (Apr 20, 2019)
15-40603242-T-C			Benign (Jul 08, 2018)
15-40604907-A-G			Likely benign (Oct 17, 2018)
15-40604974-A-G			Likely benign (Sep 22, 2018)
15-40605105-T-C			Likely benign (May 02, 2018)
15-40605155-A-G		Microcephaly 4, primary, autosomal recessive	Conflicting classifications of pathogenicity (Nov 01, 2022)
15-40605207-A-G			Likely benign (Feb 07, 2019)
15-40605388-G-A			Benign (Jul 17, 2018)
15-40606389-C-T			Likely benign (Jul 20, 2018)
15-40606406-C-T			Uncertain significance (Dec 03, 2013)
15-40606409-G-A		Inborn genetic diseases	Uncertain significance (May 11, 2022)
15-40606445-G-C		not specified • Primary Microcephaly, Recessive • Microcephaly 4, primary, autosomal recessive	Benign (Jul 14, 2021)
15-40606590-G-A			Benign (Jul 26, 2018)
15-40608606-G-T			Likely benign (Sep 22, 2018)
15-40608675-G-T			Benign (Dec 09, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
KNL1	protein_coding	protein_coding	ENST00000346991	26	70323

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.783	0.217	124692	0	97	124789	0.000389

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	-0.00813	1166	1.17e+3	1.00	0.0000556	15723
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000279	0.000279
Ashkenazi Jewish	0.00	0.00
East Asian	0.0000584	0.0000556
Finnish	0.000744	0.000742
European (Non-Finnish)	0.000605	0.000600
Middle Eastern	0.0000584	0.0000556
South Asian	0.0000328	0.0000327
Other	0.000667	0.000660

dbNSFP

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.
• Pathway: 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;RHO GTPases Activate Formins;Nucleosome assembly;RHO GTPase Effectors;Signaling by Rho GTPases;Chromosome Maintenance;Deposition of new CENPA-containing nucleosomes at the centromere;Mitotic Prometaphase;Separation of Sister Chromatids;Mitotic Anaphase;Mitotic Metaphase and Anaphase;M Phase;Cell Cycle;Resolution of Sister Chromatid Cohesion;Cell Cycle, Mitotic (Consensus)

Recessive Scores

• pRec: 0.102

Intolerance Scores

• rvis_EVS: 1.65
• rvis_percentile_EVS: 96.19

Haploinsufficiency Scores

• pHI: 0.0818
• hipred: Y
• hipred_score: 0.647
• ghis: 0.402

Essentials

• essential_gene_gene_trap: E

Mouse Genome Informatics

• Gene name: Knl1
• Phenotype: mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span)

Gene ontology

• Biological process: acrosome assembly;attachment of spindle microtubules to kinetochore;negative regulation of phosphatase activity;CENP-A containing nucleosome assembly;protein localization to kinetochore;cell division
• Cellular component: condensed chromosome kinetochore;acrosomal vesicle;nucleus;nucleoplasm;cytosol;nuclear body
• Molecular function: protein binding