Human Gene Module / Chromosome 14 / CDC42BPB

CDC42BPBCDC42 binding protein kinase beta (DMPK-like)

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
11 / 13
Rare Variants / Common Variants
37 / 0
Aliases
CDC42BPB, MRCKB
Associated Syndromes
-
Chromosome Band
14q32.32
Associated Disorders
ID, ASD
Relevance to Autism

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (PMID 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CDC42BPB as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760). Chilton et al., 2020 identified 12 heterozygous predicted deleterious variants in the CDC42BPB gene in 14 unrelated individuals with neurodevelopmental disorders including developmental delay (12/13), intellectual disability (7/13), a diagnosis of autism spectrum disorder or autistic features (8/12), hypotonia (8/11), and structural brain abnormalities (6/12).

Molecular Function

This gene encodes a serine/threonine-protein kinase that is an important downstream effector of CDC42 and plays a role in the regulation of cytoskeleton reorganization and cell migration.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to CDC42BPB (13 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations O'Roak BJ , et al. (2012) Yes -
2 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
4 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
5 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
6 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
7 Support Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort Callaghan DB , et al. (2019) Yes -
8 Recent recommendation De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype Chilton I , et al. (2020) No ASD or autistic features, ID
9 Support - Rodin RE et al. (2021) Yes -
10 Support - Mahjani B et al. (2021) Yes -
11 Support - Zhou X et al. (2022) Yes -
12 Support - M Cecilia Poli et al. () Yes -
13 Support - Karen Lob et al. () Yes ADHD, DD
Rare Variants   (37)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2726+1G>A - splice_site_variant De novo - - 38177409 M Cecilia Poli et al. ()
c.2228C>T p.Ser743Leu stop_gained De novo - - 32031333 Chilton I , et al. (2020)
c.703G>A p.Val235Met missense_variant De novo - - 33432195 Rodin RE et al. (2021)
c.823C>A p.Leu275Ile missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.2565G>C p.Gly855= missense_variant De novo - - 32031333 Chilton I , et al. (2020)
c.424G>A p.Ala142Thr missense_variant De novo - - 32031333 Chilton I , et al. (2020)
c.523G>T p.Asp175Tyr missense_variant De novo - - 32031333 Chilton I , et al. (2020)
c.879C>G p.Ile293Met missense_variant De novo - - 32031333 Chilton I , et al. (2020)
c.3783G>A p.Gly1261= missense_variant De novo - - 32031333 Chilton I , et al. (2020)
c.2599C>T p.Arg867Cys missense_variant De novo - - 32031333 Chilton I , et al. (2020)
c.2626C>T p.Arg876Trp missense_variant De novo - - 32031333 Chilton I , et al. (2020)
c.2290C>T p.Arg764Ter stop_gained De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.597-1del - splice_site_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.-26_-13del - frameshift_variant Unknown - Multiplex 32031333 Chilton I , et al. (2020)
c.93C>T p.Leu31%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.4805A>G p.Gln1602Arg missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.2612T>C p.Leu871Pro missense_variant De novo - Simplex 32031333 Chilton I , et al. (2020)
c.351G>C p.Glu117Asp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.822G>A p.Met274Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.823C>A p.Leu275Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1568dup p.Asp523GlufsTer29 frameshift_variant Unknown - - 32031333 Chilton I , et al. (2020)
c.1166C>G p.Thr389Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4951G>A p.Val1651Met missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.3388G>C p.Asp1130His missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3784C>T p.Leu1262Phe missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1891_1893dup p.Ala631dup inframe_insertion De novo - Simplex 25961944 Krumm N , et al. (2015)
c.355G>A p.Ala119Thr missense_variant Unknown - Multiplex 31038196 Callaghan DB , et al. (2019)
c.4049G>A p.Arg1350Gln missense_variant Unknown Not maternal - 32031333 Chilton I , et al. (2020)
c.5065C>T p.Pro1689Ser missense_variant Familial Maternal Multiplex 39136901 Karen Lob et al. ()
c.376G>A p.Asp126Asn missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1295G>A p.Arg432Gln missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1876A>G p.Arg626Gly missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3265G>C p.Asp1089His missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4175C>G p.Ser1392Cys missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1456_1459del p.Glu486SerfsTer4 frameshift_variant De novo - Multiplex 28263302 C Yuen RK et al. (2017)
c.1457_1460del p.Glu486AlafsTer4 frameshift_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1067dup p.Tyr357LeufsTer4 frameshift_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (PMID 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CDC42BPB as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760).

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.

1/1/2021
2
icon
2

Score remained at 2

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (PMID 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CDC42BPB as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760).

Reports Added
[The landscape of somatic mutation in cerebral cortex of autistic and neurotypical individuals revealed by ultra-deep whole-genome sequencing2021]
1/1/2020
2
icon
2

Score remained at 2

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (PMID 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CDC42BPB as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760).

Reports Added
[De novo heterozygous missense and loss-of-function variants in CDC42BPB are associated with a neurodevelopmental phenotype.2020]
10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (PMID 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CDC42BPB as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760).

Reports Added
[New Scoring Scheme]
4/1/2019
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (PMID 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CDC42BPB as a gene meeting high statistical significance with a 0.05 < FDR 0.1, meaning that this gene had a 90% chance of being a true autism gene (PMID 25363760).

Reports Added
[Whole genome sequencing and variant discovery in the ASPIRE autism spectrum disorder cohort.2019]
4/1/2017
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (PMID 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CDC42BPB as a gene meeting high statistical significance with a 0.05< FDR ?0.1, meaning that this gene had a ?90% chance of being a true autism gene (PMID 25363760).

Reports Added
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (PMID 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CDC42BPB as a gene meeting high statistical significance with a 0.05

Reports Added
[Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
4/1/2015
3
icon
3

Decreased from 3 to 3

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (PMID 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CDC42BPB as a gene meeting high statistical significance with a 0.05

Reports Added
[Excess of rare, inherited truncating mutations in autism.2015]
10/1/2014
icon
3

Increased from to 3

Description

A de novo LoF variant and a de novo missense variant that is predicted to be damaging were identified in ASD probands from the Simons Simplex Collection and the Autism Sequencing Consortium, respectively (PMID 22495309, 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified CDC42BPB as a gene meeting high statistical significance with a 0.05

Krishnan Probability Score

Score 0.49309127246741

Ranking 4299/25841 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 0.99999999963038

Ranking 84/18225 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
Iossifov Probability Score

Score 0.989

Ranking 29/239 scored genes


[Show Scoring Methodology]
Supplementary dataset S2 in the paper by Iossifov et al. (PNAS 112, E5600-E5607 (2015)) lists 239 genes with a probability of at least 0.8 of being associated with autism risk (column I). This probability metric combines the evidence from de novo likely-gene- disrupting and missense mutations and assesses it against the background mutation rate in unaffected individuals from the University of Washington’s Exome Variant Sequence database (evs.gs.washington.edu/EVS/). The list of probability scores can be found here: www.pnas.org/lookup/suppl/doi:10.1073/pnas.1516376112/- /DCSupplemental/pnas.1516376112.sd02.xlsx
Original Source
Sanders TADA Score

Score 0.25755122889934

Ranking 148/18665 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 26

Ranking 78/461 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 0.4296845921123

Ranking 1124/20870 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
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
C1ORF183 family with sequence similarity 212, member B Human Protein Binding 55924 Q9NTI7
C9ORF150 Leucine rich adaptor protein 1-like Human Protein Binding 286343 Q8IV03
FAM167A family with sequence similarity 167, member A Human Protein Binding 83648 Q96KS9
GRPR gastrin-releasing peptide receptor Human Protein Binding 2925 P30550
PRKCZ protein kinase C, zeta Human Protein Binding 5590 Q05513
UBXN2B UBX domain protein 2B Human Protein Binding 137886 Q14CS0
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