Human Gene Module / Chromosome 11 / BRSK2

BRSK2BR serine/threonine kinase 2

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
3 / 3
Rare Variants / Common Variants
11 / 0
Aliases
BRSK2, C11orf7,  PEN11B,  SAD1,  SADA,  STK29
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation, Syndromic
Chromosome Band
11p15.5
Associated Disorders
-
Relevance to Autism

A de novo loss-of-function variant in the BRSK2 gene was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo in-frame deletion variant in this gene was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Hiatt et al., 2019 identified nine individuals with rare heterozygous variants in the BRSK2 gene that presented with a neurodevelopmental disorder characterized by speech delay, intellectual disability, motor delay, autism, and behavioral abnormalities.

Molecular Function

Serine/threonine-protein kinase that plays a key role in polarization of neurons and axonogenesis, cell cycle progress and insulin secretion.

Reports related to BRSK2 (3 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Synaptic, transcriptional and chromatin genes disrupted in autism. De Rubeis S , et al. (2014) Yes -
2 Support The contribution of de novo coding mutations to autism spectrum disorder. Iossifov I , et al. (2014) Yes -
3 Recent Recommendation Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder. Hiatt SM , et al. (2019) Yes Speech delay, motor delay, developmental regressio
Rare Variants   (11)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - splice_site_variant De novo - - 25363760 De Rubeis S , et al. (2014)
- - inframe_deletion De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.730C>T p.Gln244Ter stop_gained De novo - - 30879638 Hiatt SM , et al. (2019)
c.1861C>T p.Arg621Cys missense_variant Unknown - - 30879638 Hiatt SM , et al. (2019)
c.273-1G>A p.? splice_site_variant De novo - Simplex 30879638 Hiatt SM , et al. (2019)
c.530+1G>A p.? splice_site_variant De novo - Simplex 30879638 Hiatt SM , et al. (2019)
c.194G>A p.Arg65Gln missense_variant De novo - Simplex 30879638 Hiatt SM , et al. (2019)
c.635G>A p.Gly212Glu missense_variant De novo - Simplex 30879638 Hiatt SM , et al. (2019)
c.1281_1287+5del p.? splice_site_variant Unknown - Unknown 30879638 Hiatt SM , et al. (2019)
c.1395_1396del p.Ser466GlnfsTer83 frameshift_variant De novo - Simplex 30879638 Hiatt SM , et al. (2019)
c.1532_1533del p.Glu511ValfsTer38 frameshift_variant Unknown Not maternal - 30879638 Hiatt SM , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

A de novo loss-of-function variant in the BRSK2 gene was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo in-frame deletion variant in this gene was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Hiatt et al., 2019 identified nine individuals with rare heterozygous variants in the BRSK2 gene that presented with a neurodevelopmental disorder characterized by speech delay, intellectual disability, motor delay, autism, and behavioral abnormalities.

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.

7/1/2019
4S

Initial score established: 4S

Description

A de novo loss-of-function variant in the BRSK2 gene was identified in an ASD proband from the Autism Sequencing Consortium (De Rubeis et al., 2014), while a de novo in-frame deletion variant in this gene was observed in an ASD proband from the Simons Simplex Collection (Iossifov et al., 2014). Hiatt et al., 2019 identified nine individuals with rare heterozygous variants in the BRSK2 gene that presented with a neurodevelopmental disorder characterized by speech delay, intellectual disability, motor delay, autism, and behavioral abnormalities.

Krishnan Probability Score

Score 0.53845003078592

Ranking 1458/25841 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 0.77957008109351

Ranking 4053/18225 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 0.929

Ranking 112/239 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 0.31547514598275

Ranking 192/18665 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).
Zhang D Score

Score 0.44875490790258

Ranking 936/20870 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.
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