Human Gene Module / Chromosome X / CNKSR2

CNKSR2connector enhancer of kinase suppressor of Ras 2

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
4 / 14
Rare Variants / Common Variants
32 / 0
Aliases
CNKSR2, CNK2,  KSR2,  MAGUIN
Associated Syndromes
-
Chromosome Band
Xp22.12
Associated Disorders
ADHD, ID, EPS, ASD
Relevance to Autism

Analysis of de novo variants identified in patients from the Deciphering Developmental Disorders (DDD) Study cohort, along with meta-analysis of probands from previously published studies, identified CNKSR2 as a gene exceeding genome-wide significance (P<7.0E-07) (Deciphering Developmental Disorders Study, 2017). Of the five cases with de novo loss-of-function variants in the CNKSR2 gene from the DDD cohort, two (DECIPHER IDs 260220 and 266616) were reported to have the Human Phenotype Ontology (HPO) term "Autism spectrum disorder".

Molecular Function

This gene encodes a multidomain protein that functions as a scaffold protein to mediate the mitogen-activated protein kinase pathways downstream from Ras. This gene product is induced by vitamin D and inhibits apoptosis in certain cancer cells. It may also play a role in ternary complex assembly of synaptic proteins at the postsynaptic membrane and coupling of signal transduction to membrane/cytoskeletal remodeling.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CNKSR2 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Loss-of-Function CNKSR2 Mutation Is a Likely Cause of Non-Syndromic X-Linked Intellectual Disability Houge G , et al. (2012) No ID, epilepsy/seizures, ADHD
2 Support Absent CNKSR2 causes seizures and intellectual, attention, and language deficits Vaags AK , et al. (2014) No ID, epilepsy/seizures
3 Primary Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No ASD
4 Support CNKSR2 mutation causes the X-linked epilepsy-aphasia syndrome: A case report and review of literature Sun Y , et al. (2018) Yes -
5 Support A de novo variant in the X-linked gene CNKSR2 is associated with seizures and mild intellectual disability in a female patient Polla DL , et al. (2019) No -
6 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) Yes -
7 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes -
8 Support - Higa LA et al. (2021) No ASD, ADHD
9 Support - Erata E et al. (2021) No -
10 Support - Mahjani B et al. (2021) Yes -
11 Support - Ito H et al. (2021) No -
12 Support - Chuan Z et al. (2022) No -
13 Support - Lucie Sedlackova et al. (2024) No -
14 Support - Yuting Lou et al. (2024) No ADHD, epilepsy/seizures
Rare Variants   (32)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.1954+2T>A - splice_site_variant De novo - - 28135719 et al. (2017)
c.1273C>T p.Gln425Ter stop_gained De novo - - 28135719 et al. (2017)
c.1733G>A p.Trp578Ter stop_gained De novo - - 28135719 et al. (2017)
- - copy_number_loss Familial Maternal - 34266427 Higa LA et al. (2021)
c.520-1G>A - splice_site_variant De novo - - 34266427 Higa LA et al. (2021)
c.1905-2A>G - splice_site_variant De novo - - 34266427 Higa LA et al. (2021)
c.1954+2T>A - splice_site_variant De novo - - 34266427 Higa LA et al. (2021)
c.2055+1G>A - splice_site_variant De novo - - 34266427 Higa LA et al. (2021)
c.1198C>T p.Arg400Ter stop_gained De novo - - 34266427 Higa LA et al. (2021)
c.1564C>T p.Gln522Ter stop_gained Unknown - - 35571021 Chuan Z et al. (2022)
c.175C>T p.Arg59Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
- - copy_number_loss Familial Maternal Simplex 22511892 Houge G , et al. (2012)
c.1282C>T p.Arg428Ter stop_gained Unknown - - 34615535 Mahjani B et al. (2021)
- - copy_number_loss Familial Maternal Simplex 25223753 Vaags AK , et al. (2014)
c.2782C>T p.Arg928Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
- - copy_number_loss Familial Maternal Multiplex 25223753 Vaags AK , et al. (2014)
c.2185C>T p.Arg729Ter stop_gained De novo - Simplex 30397616 Sun Y , et al. (2018)
c.2349T>G p.Tyr783Ter stop_gained De novo - Simplex 34266427 Higa LA et al. (2021)
c.2545C>T p.Arg849Ter stop_gained Familial Maternal - 34266427 Higa LA et al. (2021)
c.2304G>A p.Trp768Ter stop_gained De novo - Simplex 31414730 Polla DL , et al. (2019)
c.259del p.Thr87ProfsTer6 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.809_810del p.Val270GlyfsTer54 frameshift_variant De novo - - 28135719 et al. (2017)
c.1936_1937del p.Arg646AspfsTer2 frameshift_variant De novo - - 28135719 et al. (2017)
c.2005del p.Ala669GlnfsTer48 frameshift_variant De novo - - 34266427 Higa LA et al. (2021)
c.1653_1656del p.Asn551LysfsTer4 frameshift_variant De novo - - 34266427 Higa LA et al. (2021)
c.1988_1989del p.Arg663AsnfsTer2 frameshift_variant De novo - - 34266427 Higa LA et al. (2021)
c.2026_2027del p.Arg676AspfsTer2 frameshift_variant De novo - - 34266427 Higa LA et al. (2021)
c.1567+1G>A - splice_site_variant Familial Maternal Multiplex 38337158 Yuting Lou et al. (2024)
c.1537C>T p.Pro513Ser missense_variant Familial Maternal Simplex 34266427 Higa LA et al. (2021)
c.2693G>A p.Ser898Asn missense_variant Familial Maternal Simplex 32530565 Suzuki T et al. (2020)
c.931A>T p.Met311Leu missense_variant Familial Maternal - 38008000 Lucie Sedlackova et al. (2024)
c.453dup p.Asp152ArgfsTer8 frameshift_variant Familial Maternal Multiplex 25223753 Vaags AK , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

Analysis of de novo variants identified in patients from the Deciphering Developmental Disorders (DDD) Study cohort, along with meta-analysis of probands from previously published studies, identified CNKSR2 as a gene exceeding genome-wide significance (P<7.0E-07) (Deciphering Developmental Disorders Study, 2017). Of the five cases with de novo loss-of-function variants in the CNKSR2 gene from the DDD cohort, two (DECIPHER IDs 260220 and 266616) were reported to have the Human Phenotype Ontology (HPO) term "Autism spectrum disorder". Other recurrent HPO terms used in cases with CNKSR2 variants were joint hypermobility, global developmental delay, and abnormality of the head. Mutations in the CNKSR2 gene had previously been shown to cause a syndromic form of X-linked intellectual disability [Houge-type X-linked syndromic mental retardation (MRXSHG, OMIM 301008)] characterized by epilepsy, speech delay, and attention problems/hyperactivity (Houge et al., 2011; Vaags et al., 2014).

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."

10/1/2020
2S
icon
2S

Score remained at 2S

Description

Analysis of de novo variants identified in patients from the Deciphering Developmental Disorders (DDD) Study cohort, along with meta-analysis of probands from previously published studies, identified CNKSR2 as a gene exceeding genome-wide significance (P<7.0E-07) (Deciphering Developmental Disorders Study, 2017). Of the five cases with de novo loss-of-function variants in the CNKSR2 gene from the DDD cohort, two (DECIPHER IDs 260220 and 266616) were reported to have the Human Phenotype Ontology (HPO) term "Autism spectrum disorder". Other recurrent HPO terms used in cases with CNKSR2 variants were joint hypermobility, global developmental delay, and abnormality of the head. Mutations in the CNKSR2 gene had previously been shown to cause a syndromic form of X-linked intellectual disability [Houge-type X-linked syndromic mental retardation (MRXSHG, OMIM 301008)] characterized by epilepsy, speech delay, and attention problems/hyperactivity (Houge et al., 2011; Vaags et al., 2014).

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
7/1/2020
2S
icon
2S

Score remained at 2S

Description

Analysis of de novo variants identified in patients from the Deciphering Developmental Disorders (DDD) Study cohort, along with meta-analysis of probands from previously published studies, identified CNKSR2 as a gene exceeding genome-wide significance (P<7.0E-07) (Deciphering Developmental Disorders Study, 2017). Of the five cases with de novo loss-of-function variants in the CNKSR2 gene from the DDD cohort, two (DECIPHER IDs 260220 and 266616) were reported to have the Human Phenotype Ontology (HPO) term "Autism spectrum disorder". Other recurrent HPO terms used in cases with CNKSR2 variants were joint hypermobility, global developmental delay, and abnormality of the head. Mutations in the CNKSR2 gene had previously been shown to cause a syndromic form of X-linked intellectual disability [Houge-type X-linked syndromic mental retardation (MRXSHG, OMIM 301008)] characterized by epilepsy, speech delay, and attention problems/hyperactivity (Houge et al., 2011; Vaags et al., 2014).

Reports Added
[A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders2020]
10/1/2019
3S
icon
2S

Decreased from 3S to 2S

New Scoring Scheme
Description

Analysis of de novo variants identified in patients from the Deciphering Developmental Disorders (DDD) Study cohort, along with meta-analysis of probands from previously published studies, identified CNKSR2 as a gene exceeding genome-wide significance (P<7.0E-07) (Deciphering Developmental Disorders Study, 2017). Of the five cases with de novo loss-of-function variants in the CNKSR2 gene from the DDD cohort, two (DECIPHER IDs 260220 and 266616) were reported to have the Human Phenotype Ontology (HPO) term "Autism spectrum disorder". Other recurrent HPO terms used in cases with CNKSR2 variants were joint hypermobility, global developmental delay, and abnormality of the head. Mutations in the CNKSR2 gene had previously been shown to cause a syndromic form of X-linked intellectual disability [Houge-type X-linked syndromic mental retardation (MRXSHG, OMIM 301008)] characterized by epilepsy, speech delay, and attention problems/hyperactivity (Houge et al., 2011; Vaags et al., 2014).

Reports Added
[New Scoring Scheme]
7/1/2019
3S
icon
3S

Decreased from 3S to 3S

Description

Analysis of de novo variants identified in patients from the Deciphering Developmental Disorders (DDD) Study cohort, along with meta-analysis of probands from previously published studies, identified CNKSR2 as a gene exceeding genome-wide significance (P<7.0E-07) (Deciphering Developmental Disorders Study, 2017). Of the five cases with de novo loss-of-function variants in the CNKSR2 gene from the DDD cohort, two (DECIPHER IDs 260220 and 266616) were reported to have the Human Phenotype Ontology (HPO) term "Autism spectrum disorder". Other recurrent HPO terms used in cases with CNKSR2 variants were joint hypermobility, global developmental delay, and abnormality of the head. Mutations in the CNKSR2 gene had previously been shown to cause a syndromic form of X-linked intellectual disability [Houge-type X-linked syndromic mental retardation (MRXSHG, OMIM 301008)] characterized by epilepsy, speech delay, and attention problems/hyperactivity (Houge et al., 2011; Vaags et al., 2014).

Reports Added
[A de novo variant in the X-linked gene CNKSR2 is associated with seizures and mild intellectual disability in a female patient.2019]
10/1/2018
3S
icon
3S

Decreased from 3S to 3S

Description

Analysis of de novo variants identified in patients from the Deciphering Developmental Disorders (DDD) Study cohort, along with meta-analysis of probands from previously published studies, identified CNKSR2 as a gene exceeding genome-wide significance (P<7.0E-07) (Deciphering Developmental Disorders Study, 2017). Of the five cases with de novo loss-of-function variants in the CNKSR2 gene from the DDD cohort, two (DECIPHER IDs 260220 and 266616) were reported to have the Human Phenotype Ontology (HPO) term "Autism spectrum disorder". Other recurrent HPO terms used in cases with CNKSR2 variants were joint hypermobility, global developmental delay, and abnormality of the head. Mutations in the CNKSR2 gene had previously been shown to cause a syndromic form of X-linked intellectual disability [Houge-type X-linked syndromic mental retardation (MRXSHG, OMIM 301008)] characterized by epilepsy, speech delay, and attention problems/hyperactivity (Houge et al., 2011; Vaags et al., 2014).

Reports Added
[CNKSR2 mutation causes the X-linked epilepsy-aphasia syndrome: A case report and review of literature.2018]
1/1/2017
icon
3S

Increased from to 3S

Description

Analysis of de novo variants identified in patients from the Deciphering Developmental Disorders (DDD) Study cohort, along with meta-analysis of probands from previously published studies, identified CNKSR2 as a gene exceeding genome-wide significance (P<7.0E-07) (Deciphering Developmental Disorders Study, 2017). Of the five cases with de novo loss-of-function variants in the CNKSR2 gene from the DDD cohort, two (DECIPHER IDs 260220 and 266616) were reported to have the Human Phenotype Ontology (HPO) term "Autism spectrum disorder". Other recurrent HPO terms used in cases with CNKSR2 variants were joint hypermobility, global developmental delay, and abnormality of the head.

Krishnan Probability Score

Score 0.59722958787948

Ranking 430/25841 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 0.99974804937338

Ranking 809/18225 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 0.94278057126092

Ranking 15436/18665 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
Zhang D Score

Score 0.63625800237619

Ranking 26/20870 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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