Human Gene Module / Chromosome 2 / NCKAP1

NCKAP1NCK-associated protein 1

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
13 / 15
Rare Variants / Common Variants
36 / 0
EAGLE Score
24.75
Strong Learn More
Aliases
NCKAP1, HEM2,  NAP1,  NAP125,  p125Nap1
Associated Syndromes
-
Chromosome Band
2q32.1
Associated Disorders
ID
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

Two de novo LoF variants in the NCKAP1 gene (one nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). Transmission and de novo association (TADA) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) in Sanders et al., 2015 identified NCKAP1 as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) 0.01. A third de novo LoF variant in NCKAP1 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016. Guo et al., 2020 assembled genotype and phenotype data for 21 affected individuals from 20 unrelated families with predicted deleterious variants in NCKAP1 (including previously reported individuals from the Simons Simplex Collection and the ACGC cohorts) and found that affected individuals presented with a neurodevelopmental disorder characterized by ASD or autistic features, language and motor delay, and variable expression of intellectual or learning disability; of the 15 individuals in this cohort assessed for ASD, 10 individuals were formally diagnosed.

Molecular Function

Part of the WAVE complex that regulates lamellipodia formation. The WAVE complex regulates actin filament reorganization via its interaction with the Arp2/3 complex.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Fruit fly
Entrez Gene
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NCKAP1 (15 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary De novo gene disruptions in children on the autistic spectrum Iossifov I , et al. (2012) Yes -
2 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
3 Recent Recommendation The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
4 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
5 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
6 Support The Contribution of Mosaic Variants to Autism Spectrum Disorder Freed D and Pevsner J (2016) Yes -
7 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
8 Support Expanding the genetic heterogeneity of intellectual disability Anazi S , et al. (2017) No -
9 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No -
10 Support Homozygous deletions implicate non-coding epigenetic marks in Autism spectrum disorder Schmitz-Abe K et al. (2020) Yes -
11 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
12 Recent Recommendation NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism Guo H et al. (2020) Yes -
13 Support - Li D et al. (2022) Yes -
14 Support - Chan AJS et al. (2022) Yes ADHD
15 Support - Sheth F et al. (2023) Yes DD, ID, epilepsy/seizures
Rare Variants   (36)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - inversion De novo - Simplex 33157009 Guo H et al. (2020)
- - copy_number_loss De novo - Multiplex 33157009 Guo H et al. (2020)
c.19C>T p.Gln7Ter stop_gained De novo - - 36309498 Chan AJS et al. (2022)
c.2410C>T p.Arg804Ter stop_gained Unknown - - 33157009 Guo H et al. (2020)
c.967G>A p.Asp323Asn missense_variant Unknown - - 34968013 Li D et al. (2022)
c.3180+1G>A p.? splice_site_variant De novo - - 27824329 Wang T , et al. (2016)
c.3362C>T p.Ala1121Val missense_variant De novo - - 33157009 Guo H et al. (2020)
c.1881+1G>A - splice_site_variant Unknown - Unknown 33157009 Guo H et al. (2020)
c.1045C>T p.Arg349Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1114C>A p.Pro372Thr missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1309G>A p.Val437Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1465T>A p.Phe489Ile missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1612G>C p.Asp538His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1621G>A p.Glu541Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1630G>C p.Asp544His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2024G>C p.Arg675Thr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2129C>T p.Pro710Leu missense_variant De novo - - 33004838 Wang T et al. (2020)
c.796A>T p.Lys266Ter stop_gained De novo - Multiplex 33157009 Guo H et al. (2020)
c.5C>G p.Ser2Trp missense_variant De novo - Multiplex 33157009 Guo H et al. (2020)
c.742-3A>C - splice_region_variant De novo - Simplex 31130284 Monies D , et al. (2019)
c.1537G>A p.Ala513Thr missense_variant De novo - Unknown 33157009 Guo H et al. (2020)
c.512+3A>G - splice_region_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.427A>T p.Ile143Phe missense_variant Unknown - Simplex 37543562 Sheth F et al. (2023)
- - copy_number_loss Familial Both parents Simplex 32820185 Schmitz-Abe K et al. (2020)
c.3262G>T p.Glu1088Ter stop_gained De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.2522-3C>G - splice_region_variant Familial Maternal Simplex 33157009 Guo H et al. (2020)
c.668_671del p.Arg223IlefsTer13 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.767A>G p.Arg256Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2410C>T p.Arg804Ter stop_gained Unknown Not maternal Multiplex 33157009 Guo H et al. (2020)
c.638dup p.Tyr214IlefsTer9 frameshift_variant De novo - Multiplex 33157009 Guo H et al. (2020)
c.3222_3223insTA p.Lys1075Ter frameshift_variant De novo - Simplex 33157009 Guo H et al. (2020)
c.2131C>T p.Arg711Ter stop_gained Familial Paternal Extended multiplex 33157009 Guo H et al. (2020)
c.486_487dup p.Ala163ValfsTer5 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.2292del p.Ile765LeufsTer18 frameshift_variant Familial Maternal Simplex 33004838 Wang T et al. (2020)
c.3298G>T p.Glu1100Ter stop_gained Familial Paternal Multi-generational 28940097 Anazi S , et al. (2017)
c.2321_2322del p.Val774AlafsTer54 frameshift_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 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.

10/1/2020
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the NCKAP1 gene (one nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in NCKAP1 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020] [NCKAP1 Disruptive Variants Lead to a Neurodevelopmental Disorder with Core Features of Autism2020]
7/1/2020
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the NCKAP1 gene (one nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in NCKAP1 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

Reports Added
[Homozygous deletions implicate non-coding epigenetic marks in Autism spectrum disorder2020]
1/1/2020
1
icon
1

Score remained at 1

Description

Two de novo LoF variants in the NCKAP1 gene (one nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in NCKAP1 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

Reports Added
[Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015]
10/1/2019
2
icon
1

Decreased from 2 to 1

New Scoring Scheme
Description

Two de novo LoF variants in the NCKAP1 gene (one nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in NCKAP1 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

Reports Added
[New Scoring Scheme]
7/1/2019
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the NCKAP1 gene (one nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in NCKAP1 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019]
10/1/2017
2
icon
2

Decreased from 2 to 2

Description

Two de novo LoF variants in the NCKAP1 gene (one nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in NCKAP1 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

Reports Added
[Expanding the genetic heterogeneity of intellectual disability.2017]
10/1/2016
3
icon
2

Decreased from 3 to 2

Description

Two de novo LoF variants in the NCKAP1 gene (one nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768). A third de novo LoF variant in NCKAP1 was identified in a Chinese ASD proband from the Autism Clinical and Genetic Resources in China (ACGC) cohort in Wang et al., 2016.

Reports Added
[The Contribution of Mosaic Variants to Autism Spectrum Disorder.2016] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
1/1/2016
3
icon
3

Decreased from 3 to 3

Description

Two de novo LoF variants in the NCKAP1 gene (one nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
10/1/2014
icon
3

Increased from to 3

Description

Two de novo LoF variants in the NCKAP1 gene (one nonsense, one frameshift) were identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 25363768).

Krishnan Probability Score

Score 0.49472728577933

Ranking 3463/25841 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 0.99999999071401

Ranking 135/18225 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 0.99

Ranking 27/239 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 0.009496133417782

Ranking 28/18665 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 21

Ranking 98/461 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 0.25862254568309

Ranking 3352/20870 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
AMZ1 Archaemetzincin-1 Human Protein Binding 155185 Q400G9
CGB2 chorionic gonadotropin, beta polypeptide 2 Human Protein Binding 114336 Q6NT52
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