Human Gene Module / Chromosome 2 / KIF5C

KIF5CKinesin family member 5C

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
7 / 14
Rare Variants / Common Variants
34 / 0
Aliases
KIF5C, FLJ44735,  KIAA0531,  KINN,  MGC111478,  NKHC,  NKHC-2,  NKHC2
Associated Syndromes
-
Chromosome Band
2q23.1-q23.2
Associated Disorders
ASD, EP, EPS
Relevance to Autism

A de novo missense variant in the KIF5C gene that was predicted to be damaging was identified in an autistic proband (Awadalla et al., 2010). Inherited missense variants in this gene that were predicted to be damaging were identified in Chinese ASD probands in Li et al., 2017. Phenotypic characterization of four previously published cases (from de Ligt et al., 2013, Poirier et al., 2013, Januar et al., 2014, and Cavallin et al., 2016) and two novel cases in Michels et al., 2017 implicated KIF5C missense variants as the cause of a neurodevelopmental disorder characterized by infantile-onset epilepsy, absent speech, malformations of cortical development, and, in three cases, stereotypic hand movements.

Molecular Function

Neuron-specific kinesin heavy chain (kinesin is a microtubule-associated force-producing protein that may play a role in organelle transport)

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KIF5C (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Direct measure of the de novo mutation rate in autism and schizophrenia cohorts Awadalla P , et al. (2010) Yes -
2 Support Diagnostic exome sequencing in persons with severe intellectual disability de Ligt J , et al. (2012) No Epilepsy, ASD
3 Support Mutations in TUBG1, DYNC1H1, KIF5C and KIF2A cause malformations of cortical development and microcephaly Poirier K , et al. (2013) No Epilepsy/seizures
4 Support Somatic mutations in cerebral cortical malformations Jamuar SS , et al. (2014) No Pachygyria
5 Support Recurrent KIF5C mutation leading to frontal pachygyria without microcephaly Cavallin M , et al. (2015) No Absent speech, stereotypic hand movements, pachygy
6 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
7 Recent Recommendation Mutations of KIF5C cause a neurodevelopmental disorder of infantile-onset epilepsy, absent language, and distinctive malformations of cortical development Michels S , et al. (2017) No Absent speech, stereotypic hand movements
8 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
9 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
10 Support - Brunet T et al. (2021) No -
11 Support - Li W et al. (2021) No -
12 Support - Zhou X et al. (2022) Yes -
13 Support - Chen WX et al. (2022) Yes -
14 Support - Sanchis-Juan A et al. (2023) Yes -
Rare Variants   (34)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.510T>C p.Thr170%3D stop_lost Unknown - - 33004838 Wang T et al. (2020)
c.768T>C p.Asn256%3D stop_lost Unknown - - 33004838 Wang T et al. (2020)
c.1361A>T p.Glu454Val stop_lost Unknown - - 33004838 Wang T et al. (2020)
c.1431T>C p.Asn477%3D stop_lost Unknown - - 33004838 Wang T et al. (2020)
c.217+1G>A - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.1200C>T p.Asp400%3D stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.2331G>T p.Arg777Ser stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.2463C>T p.Asn821%3D stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.200C>T p.Ala67Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.571C>T p.Arg191Ter missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.802G>A p.Ala268Thr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.857G>A p.Arg286Gln missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1351G>C p.Asp451His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1810C>T p.Arg604Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2830G>T p.Gly944Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
C>T R802C, R872C missense_variant De novo - - 20797689 Awadalla P , et al. (2010)
c.420G>A p.Arg141Gln missense_variant De novo - - 23033978 de Ligt J , et al. (2012)
c.513G>T p.Cys172Phe missense_variant Unknown - - 25140959 Jamuar SS , et al. (2014)
c.420G>A p.Arg141Gln missense_variant De novo - - 29048727 Michels S , et al. (2017)
c.1918G>A p.Ser640= missense_variant De novo - - 31452935 Feliciano P et al. (2019)
c.1824C>T p.Leu608%3D stop_gained Familial Paternal - 33004838 Wang T et al. (2020)
c.2439G>T p.Gly814Val missense_variant Unknown - - 23033978 de Ligt J , et al. (2012)
c.420G>A p.Arg141Gln missense_variant De novo - - 26384676 Cavallin M , et al. (2015)
c.1783C>T p.Asp595= missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1344A>G p.Glu449Gly missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.2385C>T p.Ala796Val missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.2541G>A p.Arg848Lys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.160C>T p.Pro54Ser missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.323T>A p.Ile108Asn missense_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.1996G>A p.Glu666Lys missense_variant De novo - Simplex 36320054 Chen WX et al. (2022)
c.420G>A p.Leu140%3D missense_variant De novo - Unknown 33619735 Brunet T et al. (2021)
- - complex_structural_alteration Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.542T>G p.Met181Arg missense_variant Unknown - Simplex 37541188 Sanchis-Juan A et al. (2023)
c.710A>T p.Glu237Val missense_variant De novo (germline mosaicism) - Multiplex 23603762 Poirier K , et al. (2013)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

A de novo missense variant in the KIF5C gene that was predicted to be damaging was identified in an autistic proband (Awadalla et al., 2010). Inherited missense variants in this gene that were predicted to be damaging were identified in Chinese ASD probands in Li et al., 2017. Phenotypic characterization of four previously published cases (from de Ligt et al., 2013, Poirier et al., 2013, Januar et al., 2014, and Cavallin et al., 2016) and two novel cases in Michels et al., 2017 implicated KIF5C missense variants as the cause of a neurodevelopmental disorder characterized by infantile-onset epilepsy, absent speech, malformations of cortical development, and, in three cases, stereotypic hand movements.

Score Delta: Score remained at 2S

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

A de novo missense variant in the KIF5C gene that was predicted to be damaging was identified in an autistic proband (Awadalla et al., 2010). Inherited missense variants in this gene that were predicted to be damaging were identified in Chinese ASD probands in Li et al., 2017. Phenotypic characterization of four previously published cases (from de Ligt et al., 2013, Poirier et al., 2013, Januar et al., 2014, and Cavallin et al., 2016) and two novel cases in Michels et al., 2017 implicated KIF5C missense variants as the cause of a neurodevelopmental disorder characterized by infantile-onset epilepsy, absent speech, malformations of cortical development, and, in three cases, stereotypic hand movements.

1/1/2021
3S
icon
3S

Decreased from 3S to 3S

Description

A de novo missense variant in the KIF5C gene that was predicted to be damaging was identified in an autistic proband (Awadalla et al., 2010). Inherited missense variants in this gene that were predicted to be damaging were identified in Chinese ASD probands in Li et al., 2017. Phenotypic characterization of four previously published cases (from de Ligt et al., 2013, Poirier et al., 2013, Januar et al., 2014, and Cavallin et al., 2016) and two novel cases in Michels et al., 2017 implicated KIF5C missense variants as the cause of a neurodevelopmental disorder characterized by infantile-onset epilepsy, absent speech, malformations of cortical development, and, in three cases, stereotypic hand movements.

Reports Added
[De novo variants in neurodevelopmental disorders-experiences from a tertiary care center2021]
10/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

A de novo missense variant in the KIF5C gene that was predicted to be damaging was identified in an autistic proband (Awadalla et al., 2010). Inherited missense variants in this gene that were predicted to be damaging were identified in Chinese ASD probands in Li et al., 2017. Phenotypic characterization of four previously published cases (from de Ligt et al., 2013, Poirier et al., 2013, Januar et al., 2014, and Cavallin et al., 2016) and two novel cases in Michels et al., 2017 implicated KIF5C missense variants as the cause of a neurodevelopmental disorder characterized by infantile-onset epilepsy, absent speech, malformations of cortical development, and, in three cases, stereotypic hand movements.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

A de novo missense variant in the KIF5C gene that was predicted to be damaging was identified in an autistic proband (Awadalla et al., 2010). Inherited missense variants in this gene that were predicted to be damaging were identified in Chinese ASD probands in Li et al., 2017. Phenotypic characterization of four previously published cases (from de Ligt et al., 2013, Poirier et al., 2013, Januar et al., 2014, and Cavallin et al., 2016) and two novel cases in Michels et al., 2017 implicated KIF5C missense variants as the cause of a neurodevelopmental disorder characterized by infantile-onset epilepsy, absent speech, malformations of cortical development, and, in three cases, stereotypic hand movements.

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
7/1/2018
icon
4S

Increased from to 4S

Description

A de novo missense variant in the KIF5C gene that was predicted to be damaging was identified in an autistic proband (Awadalla et al., 2010). Inherited missense variants in this gene that were predicted to be damaging were identified in Chinese ASD probands in Li et al., 2017. Phenotypic characterization of four previously published cases (from de Ligt et al., 2013, Poirier et al., 2013, Januar et al., 2014, and Cavallin et al., 2016) and two novel cases in Michels et al., 2017 implicated KIF5C missense variants as the cause of a neurodevelopmental disorder characterized by infantile-onset epilepsy, absent speech, malformations of cortical development, and, in three cases, stereotypic hand movements.

Krishnan Probability Score

Score 0.61320097232496

Ranking 146/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.99951559715187

Ranking 932/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.94145518732924

Ranking 14939/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Larsen Cumulative Evidence Score

Score 2

Ranking 393/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Original Source
Zhang D Score

Score 0.42920690030661

Ranking 1130/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
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