KIF5C
protein-codingkinesin family member 5C, the group of Kinesins
Gene summary
The protein encoded by this gene is a kinesin heavy chain subunit involved in the transport of cargo within the central nervous system. The encoded protein, which acts as a tetramer by associating with another heavy chain and two light chains, interacts with protein kinase CK2. Mutations in this gene have been associated with complex cortical dysplasia with other brain malformations-2. Two transcript variants, one protein-coding and the other non-protein coding, have been found for this gene. [provided by RefSeq, Jul 2015]
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~151.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0014116
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0014116
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0014116
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0014116
Submitter: ClinGen
KIF5C was originally reported in cases of microcephaly and polymicrogyria in 2013 (PMID: 23603762). Reported variants of KIF5C are mostly on the Glu237 residue, which localizes to the microtubule binding domain. These include the p.Glu237Val variant initially reported in four siblings (presumed maternal germline mosaicism) and five independent cases with the de novo p.Glu237Lys variant (PMID: 24812067, 26384676, 29048727, 32562872). These individuals all have malformations of cortical development variably characterized as polymicrogyria and pachygyria, which are frontally predominant in distribution. Microcephaly may or may not be present. The p.Glu237Val change was shown to disrupt microtubule-dependent ATP hydrolysis of the KIF5C protein in vitro (PMID: 23603762). Total score was in the Limited range; however, in light of the mutation hotspot (Glu237), with the recurrent de novo p.Glu237 variant, it was interpreted that there is moderate level of evidence to suggest that KIF5C is associated with complex cortical dysplasia with other brain malformations 2. This has been approved by the ClinGen Brain Malformations Gene Curation Expert Panel on 01/25/2022 (SOP Version 8).
Clinical Genomic Database (CGD)
Manifestation: 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
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KIF5C variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_004522.3. 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 | 2 | 44 | 4 | 50 | ||
| missense | 1 | 6 | 113 | 17 | 1 | 138 |
| nonsense | 1 | 3 | 4 | |||
| start loss | 1 | 1 | ||||
| frameshift | 2 | 3 | 5 | |||
| splice donor/acceptor (+/-2bp) | 1 | 3 | 4 | |||
| Total | 1 | 10 | 125 | 61 | 5 | 202 |
Highest pathogenic variant AF is 0.0000065715976
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_004513.1 | 25 | MANE Select | |
| Ensembl | ENSP00000393379.1 | 25 | MANE Select | |
| Ensembl | ENSP00000503401.1 | 18 | Standard | |
| Ensembl | ENSP00000504288.1 | 13 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Dopaminergic synapse - Homo sapiens (human)
- Endocytosis - Homo sapiens (human)
Biological Process
- organelle organization
- microtubule-based movement
- axon guidance
- motor neuron axon guidance
- synaptic vesicle transport
Molecular Function
- microtubule motor activity
- protein binding
- ATP binding
- microtubule binding
- ATP-dependent microtubule motor activity, plus-end-directed
Cellular Component
- kinesin complex
- microtubule
- dendrite cytoplasm
- ciliary rootlet
- neuronal cell body
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000435030
- Coding exons
- 25
- Length
- 250455
- Individuals with no LoFs
- 124682
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 12
- Defined
- 124694
- p
- 0.0000481
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 4.05 | 253 | 511 | 0.495 | 0.0000285 | 6320 |
| Missense (PolyPhen) | 44 | 168.59 | 0.26098 | 1955 | ||
| Synonymous | 0.426 | 183 | 190 | 0.961 | 0.0000107 | 1686 |
| Loss of Function | 6.54 | 2 | 53.7 | 0.0373 | 0.00000279 | 680 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00013 | 0.00013 | rare |
| Latino/Admixed American | 0.000058 | 0.000058 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0.00011 | 0.00011 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000045 | 0.000044 | rare |
| South Asian | 0.000037 | 0.000033 | rare |
| Other | 0 | 0.0 | absent |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Involved in synaptic transmission (PubMed:24812067). Mediates dendritic trafficking of mRNAs (By similarity). Kinesin is a microtubule-associated force-producing protein that may play a role in organelle transport. Required for anterograde axonal transportation of MAPK8IP3/JIP3 which is essential for MAPK8IP3/JIP3 function in axon elongation (By similarity). {ECO:0000250|UniProtKB:P28738, ECO:0000250|UniProtKB:P56536, ECO:0000269|PubMed:24812067}.;
- Disease
- DISEASE: Cortical dysplasia, complex, with other brain malformations 2 (CDCBM2) [MIM:615282]: A disorder of aberrant neuronal migration and disturbed axonal guidance. Clinical features include intrauterine growth retardation, fetal akinesia, seizures, microcephaly, lack of psychomotor development, and arthrogryposis. Brain imaging shows malformations of cortical development, including polymicrogyria, gyral simplification, and thin corpus callosum. {ECO:0000269|PubMed:23033978, ECO:0000269|PubMed:23603762, ECO:0000269|PubMed:24812067, ECO:0000269|PubMed:29048727}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Essentials
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.942
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |