Human Gene Module / Chromosome 2 / NCKAP1

NCKAP1NCK-associated protein 1

Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 7
Rare Variants / Common Variants
6 / 0
Aliases
NCKAP1, HEM2,  NAP1,  NAP125,  p125Nap1
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
2q32.1
Associated Disorders
-
Relevance to Autism

Two de novo loss-of-function variants in the NCKAP1 gene have been identified in ASD probands from the Simons Simplex Collection (refs).

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.

Reports related to NCKAP1 (7 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 The Contribution of Mosaic Variants to Autism Spectrum Disorder. Freed D and Pevsner J (2016) Yes -
6 Support De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
7 Support Expanding the genetic heterogeneity of intellectual disability. Anazi S , et al. (2017) No -
Rare Variants   (6)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.3262G>T p.Glu1088Ter stop_gained De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.2321_2322del p.Gln774fs frameshift_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.767A>G p.Arg256Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.503_504insTG p.His168fs frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.3180+1G>A p.? splice_site_variant De novo - - 27824329 Wang T , et al. (2016)
c.3298G>T p.Glu1100Ter stop_gained Familial - Multi-generational 28940097 Anazi S , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

2

Score Delta: Score remained at 2.1

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.

10/1/2017
2
icon
2

Score remained at 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.

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.

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).

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.
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
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
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).
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.
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.
CNVs associated with NCKAP1(1 CNVs)
2q32.1 21 Deletion-Duplication 35  /  171
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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