Human Gene Module / Chromosome 9 / KANK1

KANK1KN motif and ankyrin repeat domains 1

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
10 / 12
Rare Variants / Common Variants
16 / 0
Aliases
KANK1, RP11-130C19.4,  ANKRD15,  CPSQ2,  KANK
Associated Syndromes
-
Chromosome Band
9p24.3
Associated Disorders
ADHD, ID
Relevance to Autism

Paternally-inherited deletions in the KANK1 gene have been identified in a male proband with ASD, intellectual disability, and motor and speech delays (Vanzo et al., 2013), as well as in nine affected children from a four-generation family presenting with cerebral palsy, quadriplegia, and intellectual disability (Lerer et al., 2005).

Molecular Function

The protein encoded by this gene belongs to the Kank family of proteins, which contain multiple ankyrin repeat domains. This family member functions in cytoskeleton formation by regulating actin polymerization. Mutations in this gene cause cerebral palsy spastic quadriplegic type 2, a central nervous system development disorder.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to KANK1 (12 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Deletion of the ANKRD15 gene at 9p24.3 causes parent-of-origin-dependent inheritance of familial cerebral palsy Lerer I , et al. (2005) No Cerebral palsy
2 Support Refinement and discovery of new hotspots of copy-number variation associated with autism spectrum disorder Girirajan S , et al. (2013) Yes -
3 Primary Familial KANK1 deletion that does not follow expected imprinting pattern Vanzo RJ , et al. (2013) Yes ID
4 Support Exome sequencing in multiplex autism families suggests a major role for heterozygous truncating mutations Toma C , et al. (2013) Yes -
5 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
6 Support Genes that Affect Brain Structure and Function Identified by Rare Variant Analyses of Mendelian Neurologic Disease Karaca E , et al. (2015) No Brain abnormalities, hypotonia
7 Recent Recommendation Clinical significance of copy number variants involving KANK1 in patients with neurodevelopmental disorders Vanzo RJ , et al. (2018) Yes -
8 Negative Association Small interstitial 9p24.3 deletions principally involving KANK1 are likely benign copy number variants Wallis MJ , et al. (2019) Yes -
9 Support Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks Ruzzo EK , et al. (2019) Yes -
10 Support - Capkova Z et al. (2021) Yes ADHD
11 Support - Hu C et al. (2022) Yes -
12 Support - Zhou X et al. (2022) Yes -
Rare Variants   (16)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_gain Unknown - Simplex 33455084 Capkova Z et al. (2021)
- - copy_number_loss Familial Paternal Simplex 23454270 Vanzo RJ , et al. (2013)
c.2287C>A p.Gln763Lys missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3295A>G p.Thr1099Ala missense_variant De novo - - 35982159 Zhou X et al. (2022)
- - copy_number_gain Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_gain Familial Paternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Maternal Simplex 23375656 Girirajan S , et al. (2013)
- - copy_number_gain Familial Paternal Multiplex 23375656 Girirajan S , et al. (2013)
- - copy_number_loss Familial Maternal Multiplex 23375656 Girirajan S , et al. (2013)
c.1852del p.Thr618GlnfsTer3 frameshift_variant Unknown - - 35741772 Hu C et al. (2022)
c.1490C>T p.Ser497Leu missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
- - copy_number_loss Familial Paternal Multi-generational 16301218 Lerer I , et al. (2005)
c.1742G>A p.Cys581Tyr missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2896+2T>G - splice_site_variant Familial Maternal Simplex 31398340 Ruzzo EK , et al. (2019)
c.3789G>C p.Gln1263His missense_variant Familial Maternal Multiplex 23999528 Toma C , et al. (2013)
c.2763C>G p.Ile921Met missense_variant Familial Both parents Simplex 26539891 Karaca E , et al. (2015)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

Paternally-inherited deletions in the KANK1 gene have been identified in a male proband with ASD, intellectual disability, and motor and speech delays (Vanzo et al., 2013), as well as in nine affected children from a four-generation family presenting with cerebral palsy, quadriplegia, and intellectual disability (Lerer et al., 2005). Inherited CNVs disrupting at least one exon of the KANK1 gene were identified in eight unrelated ASD probands (two with deletions, six with duplications) in Girirajan et al., 2013; in contrast, 3 exon-disruptive KANK1 CNVs (all duplications) were observed in 2,670 controls (p = 0.103). Genetic and clinical description of 28 individuals with KANK1 CNVs (16 with deletions, 12 with duplications; all individuals presented with ASD and/or developmental delay/intellectual disability) from a database of 22,054 patients, in conjunction with a review of the literature, in Vanzo et al., 2018 led the authors to conclude that KANK1 CNVs may be a risk factor for ASD, especially when the coding region of the shorter alternate KANK1 transcript is affected.

Score Delta: Score remained at 2

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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

Paternally-inherited deletions in the KANK1 gene have been identified in a male proband with ASD, intellectual disability, and motor and speech delays (Vanzo et al., 2013), as well as in nine affected children from a four-generation family presenting with cerebral palsy, quadriplegia, and intellectual disability (Lerer et al., 2005). Inherited CNVs disrupting at least one exon of the KANK1 gene were identified in eight unrelated ASD probands (two with deletions, six with duplications) in Girirajan et al., 2013; in contrast, 3 exon-disruptive KANK1 CNVs (all duplications) were observed in 2,670 controls (p = 0.103). Genetic and clinical description of 28 individuals with KANK1 CNVs (16 with deletions, 12 with duplications; all individuals presented with ASD and/or developmental delay/intellectual disability) from a database of 22,054 patients, in conjunction with a review of the literature, in Vanzo et al., 2018 led the authors to conclude that KANK1 CNVs may be a risk factor for ASD, especially when the coding region of the shorter alternate KANK1 transcript is affected.

1/1/2021
3
icon
3

Decreased from 3 to 3

Description

Paternally-inherited deletions in the KANK1 gene have been identified in a male proband with ASD, intellectual disability, and motor and speech delays (Vanzo et al., 2013), as well as in nine affected children from a four-generation family presenting with cerebral palsy, quadriplegia, and intellectual disability (Lerer et al., 2005). Inherited CNVs disrupting at least one exon of the KANK1 gene were identified in eight unrelated ASD probands (two with deletions, six with duplications) in Girirajan et al., 2013; in contrast, 3 exon-disruptive KANK1 CNVs (all duplications) were observed in 2,670 controls (p = 0.103). Genetic and clinical description of 28 individuals with KANK1 CNVs (16 with deletions, 12 with duplications; all individuals presented with ASD and/or developmental delay/intellectual disability) from a database of 22,054 patients, in conjunction with a review of the literature, in Vanzo et al., 2018 led the authors to conclude that KANK1 CNVs may be a risk factor for ASD, especially when the coding region of the shorter alternate KANK1 transcript is affected.

Reports Added
[Duplication of 9p24.3 in three unrelated patients and their phenotypes, considering affected genes, and similar recurrent variants2021]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

Paternally-inherited deletions in the KANK1 gene have been identified in a male proband with ASD, intellectual disability, and motor and speech delays (Vanzo et al., 2013), as well as in nine affected children from a four-generation family presenting with cerebral palsy, quadriplegia, and intellectual disability (Lerer et al., 2005). Inherited CNVs disrupting at least one exon of the KANK1 gene were identified in eight unrelated ASD probands (two with deletions, six with duplications) in Girirajan et al., 2013; in contrast, 3 exon-disruptive KANK1 CNVs (all duplications) were observed in 2,670 controls (p = 0.103). Genetic and clinical description of 28 individuals with KANK1 CNVs (16 with deletions, 12 with duplications; all individuals presented with ASD and/or developmental delay/intellectual disability) from a database of 22,054 patients, in conjunction with a review of the literature, in Vanzo et al., 2018 led the authors to conclude that KANK1 CNVs may be a risk factor for ASD, especially when the coding region of the shorter alternate KANK1 transcript is affected.

Reports Added
[New Scoring Scheme]
7/1/2019
4
icon
4

Decreased from 4 to 4

Description

Paternally-inherited deletions in the KANK1 gene have been identified in a male proband with ASD, intellectual disability, and motor and speech delays (Vanzo et al., 2013), as well as in nine affected children from a four-generation family presenting with cerebral palsy, quadriplegia, and intellectual disability (Lerer et al., 2005). Inherited CNVs disrupting at least one exon of the KANK1 gene were identified in eight unrelated ASD probands (two with deletions, six with duplications) in Girirajan et al., 2013; in contrast, 3 exon-disruptive KANK1 CNVs (all duplications) were observed in 2,670 controls (p = 0.103). Genetic and clinical description of 28 individuals with KANK1 CNVs (16 with deletions, 12 with duplications; all individuals presented with ASD and/or developmental delay/intellectual disability) from a database of 22,054 patients, in conjunction with a review of the literature, in Vanzo et al., 2018 led the authors to conclude that KANK1 CNVs may be a risk factor for ASD, especially when the coding region of the shorter alternate KANK1 transcript is affected.

Reports Added
[Inherited and De Novo Genetic Risk for Autism Impacts Shared Networks.2019]
1/1/2019
4
icon
4

Decreased from 4 to 4

Description

Paternally-inherited deletions in the KANK1 gene have been identified in a male proband with ASD, intellectual disability, and motor and speech delays (Vanzo et al., 2013), as well as in nine affected children from a four-generation family presenting with cerebral palsy, quadriplegia, and intellectual disability (Lerer et al., 2005). Inherited CNVs disrupting at least one exon of the KANK1 gene were identified in eight unrelated ASD probands (two with deletions, six with duplications) in Girirajan et al., 2013; in contrast, 3 exon-disruptive KANK1 CNVs (all duplications) were observed in 2,670 controls (p = 0.103). Genetic and clinical description of 28 individuals with KANK1 CNVs (16 with deletions, 12 with duplications; all individuals presented with ASD and/or developmental delay/intellectual disability) from a database of 22,054 patients, in conjunction with a review of the literature, in Vanzo et al., 2018 led the authors to conclude that KANK1 CNVs may be a risk factor for ASD, especially when the coding region of the shorter alternate KANK1 transcript is affected.

Reports Added
[Small interstitial 9p24.3 deletions principally involving KANK1 are likely benign copy number variants.2019]
7/1/2018
icon
4

Increased from to 4

Description

Paternally-inherited deletions in the KANK1 gene have been identified in a male proband with ASD, intellectual disability, and motor and speech delays (Vanzo et al., 2013), as well as in nine affected children from a four-generation family presenting with cerebral palsy, quadriplegia, and intellectual disability (Lerer et al., 2005). Inherited CNVs disrupting at least one exon of the KANK1 gene were identified in eight unrelated ASD probands (two with deletions, six with duplications) in Girirajan et al., 2013; in contrast, 3 exon-disruptive KANK1 CNVs (all duplications) were observed in 2,670 controls (p = 0.103). Genetic and clinical description of 28 individuals with KANK1 CNVs (16 with deletions, 12 with duplications; all individuals presented with ASD and/or developmental delay/intellectual disability) from a database of 22,054 patients, in conjunction with a review of the literature, in Vanzo et al., 2018 led the authors to conclude that KANK1 CNVs may be a risk factor for ASD, especially when the coding region of the shorter alternate KANK1 transcript is affected.

Krishnan Probability Score

Score 0.53534863452217

Ranking 1493/25841 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
Sanders TADA Score

Score 0.79957472623377

Ranking 2201/18665 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 6

Ranking 258/461 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 -0.24295795460193

Ranking 16249/20870 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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