Human Gene Module / Chromosome 11 / NAV2

NAV2neuron navigator 2

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
9 / 14
Rare Variants / Common Variants
27 / 0
Aliases
NAV2, HELAD1,  POMFIL2,  RAINB1,  STEERIN2,  UNC53H2
Associated Syndromes
-
Chromosome Band
11p15.1
Associated Disorders
-
Relevance to Autism

De novo variants in the NAV2 gene, including two missense variants and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator, have been observed in ASD probands (Sanders et al., 2012; O'Roak et al., 2012; Iossifov et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.78E-02 (Takata et al., 2016).

Molecular Function

This gene encodes a member of the neuron navigator gene family, which may play a role in cellular growth and migration. The protein encoded by the NAV2 gene possesses 3' to 5' helicase activity and exonuclease activity and is involved in neuronal development, specifically in the development of different sensory organs.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to NAV2 (14 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Sensory deficits in mice hypomorphic for a mammalian homologue of unc-53 Peeters PJ , et al. (2004) No -
2 Primary De novo mutations revealed by whole-exome sequencing are strongly associated with autism Sanders SJ , et al. (2012) Yes -
3 Support Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations O'Roak BJ , et al. (2012) Yes -
4 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Recent Recommendation De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia Takata A , et al. (2016) No -
6 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
7 Support Neurogenetic analysis of childhood disintegrative disorder Gupta AR , et al. (2017) No -
8 Support Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder Lim ET , et al. (2017) Yes -
9 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
10 Support - Woodbury-Smith M et al. (2022) Yes -
11 Support - Accogli A et al. (2022) No -
12 Support - Zhou X et al. (2022) Yes -
13 Support - Wang J et al. (2023) Yes -
14 Support - Shenglan Li et al. (2024) No -
Rare Variants   (27)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.4875+1G>A - splice_site_variant Unknown - - 27824329 Wang T , et al. (2016)
c.2596G>A p.Val866Ile missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1551G>A p.Ala517%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.4677G>A p.Ser1559%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.45C>A p.Pro15%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.3332A>G p.Lys1111Arg missense_variant De novo - Simplex 37393044 Wang J et al. (2023)
c.125G>A p.Arg42His missense_variant De novo - Multiplex 28714951 Lim ET , et al. (2017)
c.5793C>T p.Leu1931%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.2432G>A p.Arg811Gln missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.2924G>A p.Arg975Gln missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.892C>T p.Arg298Cys missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.1093C>T p.Arg365Trp missense_variant Unknown - - 35205252 Woodbury-Smith M et al. (2022)
c.587_589dup p.Gln196dup inframe_insertion De novo - Simplex 35982159 Zhou X et al. (2022)
c.3446G>A p.Ser1149Asn missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.3707G>A p.Ser1236Asn missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.4555C>T p.Arg1519Cys missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.6419C>T p.Ser2140Leu missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.6878G>A p.Arg2293Gln missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.6136C>T p.Arg2046Trp missense_variant De novo - Simplex 28392909 Gupta AR , et al. (2017)
c.4284C>T p.Ser1428%3D synonymous_variant De novo - Multiplex 35982159 Zhou X et al. (2022)
c.6210C>T p.Asp2070= synonymous_variant De novo - Simplex 22495309 O'Roak BJ , et al. (2012)
c.7405G>A p.Asp2469Asn missense_variant De novo - Simplex 22495306 Sanders SJ , et al. (2012)
c.2441G>A p.Arg814Gln missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.6580del p.Ile2194Ter frameshift_variant Familial Paternal - 38593811 Shenglan Li et al. (2024)
c.6757delA p.Ile12253Ter frameshift_variant Familial Paternal Simplex 35218524 Accogli A et al. (2022)
c.5011_5012del p.Leu1672TrpfsTer2 frameshift_variant Familial Maternal - 38593811 Shenglan Li et al. (2024)
c.5179_5180delAG p.Leu1728TrpfsTer2 frameshift_variant Familial Maternal Simplex 35218524 Accogli A et al. (2022)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

De novo variants in the NAV2 gene, including two missense variants and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator, have been observed in ASD probands (Sanders et al., 2012; O'Roak et al., 2012; Iossifov et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.78E-02 (Takata et al., 2016). The NAV2/unc53H2 hypomorphic mouse showed a general impaired acuity of several sensory systems (olfactory, auditory, visual and pain sensation), which in the case of the visual system was corroborated by the morphological observation of hypoplasia of the optic nerve (Peeters et al., 2004).

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.

10/1/2019
3
icon
2

Decreased from 3 to 2

New Scoring Scheme
Description

De novo variants in the NAV2 gene, including two missense variants and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator, have been observed in ASD probands (Sanders et al., 2012; O'Roak et al., 2012; Iossifov et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.78E-02 (Takata et al., 2016). The NAV2/unc53H2 hypomorphic mouse showed a general impaired acuity of several sensory systems (olfactory, auditory, visual and pain sensation), which in the case of the visual system was corroborated by the morphological observation of hypoplasia of the optic nerve (Peeters et al., 2004).

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

Decreased from 3 to 3

Description

De novo variants in the NAV2 gene, including two missense variants and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator, have been observed in ASD probands (Sanders et al., 2012; O'Roak et al., 2012; Iossifov et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.78E-02 (Takata et al., 2016). The NAV2/unc53H2 hypomorphic mouse showed a general impaired acuity of several sensory systems (olfactory, auditory, visual and pain sensation), which in the case of the visual system was corroborated by the morphological observation of hypoplasia of the optic nerve (Peeters et al., 2004).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
7/1/2017
3
icon
3

Decreased from 3 to 3

Description

De novo variants in the NAV2 gene, including two missense variants and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator, have been observed in ASD probands (Sanders et al., 2012; O'Roak et al., 2012; Iossifov et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.78E-02 (Takata et al., 2016). The NAV2/unc53H2 hypomorphic mouse showed a general impaired acuity of several sensory systems (olfactory, auditory, visual and pain sensation), which in the case of the visual system was corroborated by the morphological observation of hypoplasia of the optic nerve (Peeters et al., 2004).

Reports Added
[Rates, distribution and implications of postzygotic mosaic mutations in autism spectrum disorder.2017]
4/1/2017
3
icon
3

Decreased from 3 to 3

Description

De novo variants in the NAV2 gene, including two missense variants and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator, have been observed in ASD probands (Sanders et al., 2012; O'Roak et al., 2012; Iossifov et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.78E-02 (Takata et al., 2016). The NAV2/unc53H2 hypomorphic mouse showed a general impaired acuity of several sensory systems (olfactory, auditory, visual and pain sensation), which in the case of the visual system was corroborated by the morphological observation of hypoplasia of the optic nerve (Peeters et al., 2004).

Reports Added
[De novo mutations revealed by whole-exome sequencing are strongly associated with autism.2012] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations.2012] [De Novo Synonymous Mutations in Regulatory Elements Contribute to the Genetic Etiology of Autism and Schizophrenia.2016] [Sensory deficits in mice hypomorphic for a mammalian homologue of unc-53.2004] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Neurogenetic analysis of childhood disintegrative disorder.2017]
10/1/2016
3
icon
3

Decreased from 3 to 3

Description

De novo variants in the NAV2 gene, including two missense variants and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator, have been observed in ASD probands (Sanders et al., 2012; O'Roak et al., 2012; Iossifov et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.78E-02 (Takata et al., 2016). The NAV2/unc53H2 hypomorphic mouse showed a general impaired acuity of several sensory systems (olfactory, auditory, visual and pain sensation), which in the case of the visual system was corroborated by the morphological observation of hypoplasia of the optic nerve (Peeters et al., 2004).

Reports Added
[De novo genic mutations among a Chinese autism spectrum disorder cohort.2016]
7/1/2016
3
icon
3

Decreased from 3 to 3

Description

De novo variants in the NAV2 gene, including two missense variants and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator, have been observed in ASD probands (Sanders et al., 2012; O'Roak et al., 2012; Iossifov et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.78E-02 (Takata et al., 2016). The NAV2/unc53H2 hypomorphic mouse showed a general impaired acuity of several sensory systems (olfactory, auditory, visual and pain sensation), which in the case of the visual system was corroborated by the morphological observation of hypoplasia of the optic nerve (Peeters et al., 2004).

Reports Added
[Sensory deficits in mice hypomorphic for a mammalian homologue of unc-53.2004]
4/1/2016
icon
3

Increased from to 3

Description

De novo variants in the NAV2 gene, including two missense variants and a synonymous variant predicted in PMID 26938441 to affect splicing regulation by altering an exonic splicing regulator, have been observed in ASD probands (Sanders et al., 2012; O'Roak et al., 2012; Iossifov et al., 2014). Evaluation of the statistical significance of observing multiple functional de novo variants in this gene, taking into account gene length and local sequence context to determine the expected number of variants, generated a p-value of 1.78E-02 (Takata et al., 2016). The NAV2/unc53H2 hypomorphic mouse showed a general impaired acuity of several sensory systems (olfactory, auditory, visual and pain sensation), which in the case of the visual system was corroborated by the morphological observation of hypoplasia of the optic nerve (Peeters et al., 2004).

Krishnan Probability Score

Score 0.51514829870164

Ranking 1763/25841 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 0.99751712507028

Ranking 1314/18225 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 0.897

Ranking 143/239 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 0.91000338922639

Ranking 7529/18665 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 0.18900354939991

Ranking 4443/20870 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
Submit New Gene

Report an Error