Human Gene Module / Chromosome 12 / ANKS1B

ANKS1Bankyrin repeat and sterile alpha motif domain containing 1B

SFARI Gene Score
2S
Strong Candidate, Syndromic Criteria 2.1, Syndromic
Autism Reports / Total Reports
6 / 7
Rare Variants / Common Variants
17 / 0
Aliases
ANKS1B, AIDA,  AIDA-1,  ANKS2,  EB-1,  EB1,  cajalin-2
Associated Syndromes
-
Chromosome Band
12q23.1
Associated Disorders
-
Relevance to Autism

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module. Sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism; this finding was further validated by exome sequencing of an independent cohort of 505 ASD cases and 491 controls (Li et al., 2014).

Molecular Function

This gene encodes a multi-domain protein that is predominantly expressed in brain and testis. This protein interacts with amyloid beta protein precursor (AbetaPP) and may have a role in normal brain development, and in the pathogenesis of Alzheimer's disease.

External Links
Gene CardOpen Targets PlatformgnomAD browserSynGO portalPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome InformaticsAllen Brain Atlas
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ANKS1B (7 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Primary Integrated systems analysis reveals a molecular network underlying autism spectrum disorders Li J , et al. (2015) Yes -
2 Recent Recommendation Haploinsufficiency in the ANKS1B gene encoding AIDA-1 leads to a neurodevelopmental syndrome Carbonell AU , et al. (2019) Yes -
3 Support Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort da Silva Montenegro EM , et al. (2019) Yes -
4 Support A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders Suzuki T et al. (2020) Yes -
5 Support - Cirnigliaro M et al. (2023) Yes -
6 Recent Recommendation - Chang Hoon Cho et al. (2023) Yes -
7 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (17)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - copy_number_loss De novo - - 31388001 Carbonell AU , et al. (2019)
- - copy_number_loss Unknown - - 31388001 Carbonell AU , et al. (2019)
- - copy_number_loss Familial - - 31388001 Carbonell AU , et al. (2019)
- - nonsynonymous_variant Unknown - Unknown 25549968 Li J , et al. (2015)
- - copy_number_loss Familial - Simplex 31388001 Carbonell AU , et al. (2019)
- - copy_number_loss Familial Maternal - 31388001 Carbonell AU , et al. (2019)
- - copy_number_loss Familial Paternal - 31388001 Carbonell AU , et al. (2019)
c.3367-2A>G - splice_site_variant Unknown - - 39039281 Axel Schmidt et al. (2024)
c.50C>T p.Ala17Val missense_variant Unknown - Unknown 25549968 Li J , et al. (2015)
- - copy_number_loss Familial Paternal Simplex 31388001 Carbonell AU , et al. (2019)
- - copy_number_loss Familial Paternal Multiplex 31388001 Carbonell AU , et al. (2019)
c.2240C>G p.Ser747Cys missense_variant Unknown - Unknown 25549968 Li J , et al. (2015)
c.85-6C>T p.? splice_region_variant Unknown - Simplex 32530565 Suzuki T et al. (2020)
c.140T>C p.Ile47Thr missense_variant De novo - Simplex 32530565 Suzuki T et al. (2020)
AGT>A - frameshift_variant Familial Maternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.284C>A p.Pro95His missense_variant De novo - Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1568G>A p.Arg523Gln missense_variant De novo - Simplex 31696658 da Silva Montenegro EM , et al. (2019)
Common Variants  

No common variants reported.

SFARI Gene score
2S

Strong Candidate, Syndromic

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module. Sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism; this finding was further validated by exome sequencing of an independent cohort of 505 ASD cases and 491 controls (Li et al., 2014). All three non-synonymous variants in ANKS1B described in this study had GERP++ conservation scores > 3.31; furthermore, of the three variants, one variant was not reported in 1000 Genomes (as of Jan/ Feb. 2013) or in SNP, while a second was not reported in 1000 Genomes, but was reported in dbSNP. Carbonell et al., 2019 described individuals with heterozygous monogenic deletions affecting the ANKS1B gene who presented with a spectrum of neurodevelopmental phenotypes, including ASD, ADHD, and developmental delay, as well as dysmorphic features; in the same report, the authors demonstrated that a transgenic mouse model of Anks1b haploinsufficiency recapitulated a range of patient phenotypes, including social deficits, hyperactivity, and sensorimotor dysfunction.

Score Delta: Score remained at 2S

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.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2022
3S
icon
2S

Decreased from 3S to 2S

Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module. Sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism; this finding was further validated by exome sequencing of an independent cohort of 505 ASD cases and 491 controls (Li et al., 2014). All three non-synonymous variants in ANKS1B described in this study had GERP++ conservation scores > 3.31; furthermore, of the three variants, one variant was not reported in 1000 Genomes (as of Jan/ Feb. 2013) or in SNP, while a second was not reported in 1000 Genomes, but was reported in dbSNP. Carbonell et al., 2019 described individuals with heterozygous monogenic deletions affecting the ANKS1B gene who presented with a spectrum of neurodevelopmental phenotypes, including ASD, ADHD, and developmental delay, as well as dysmorphic features; in the same report, the authors demonstrated that a transgenic mouse model of Anks1b haploinsufficiency recapitulated a range of patient phenotypes, including social deficits, hyperactivity, and sensorimotor dysfunction.

7/1/2020
3S
icon
3S

Decreased from 3S to 3S

Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module. Sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism; this finding was further validated by exome sequencing of an independent cohort of 505 ASD cases and 491 controls (Li et al., 2014). All three non-synonymous variants in ANKS1B described in this study had GERP++ conservation scores > 3.31; furthermore, of the three variants, one variant was not reported in 1000 Genomes (as of Jan/ Feb. 2013) or in SNP, while a second was not reported in 1000 Genomes, but was reported in dbSNP. Carbonell et al., 2019 described individuals with heterozygous monogenic deletions affecting the ANKS1B gene who presented with a spectrum of neurodevelopmental phenotypes, including ASD, ADHD, and developmental delay, as well as dysmorphic features; in the same report, the authors demonstrated that a transgenic mouse model of Anks1b haploinsufficiency recapitulated a range of patient phenotypes, including social deficits, hyperactivity, and sensorimotor dysfunction.

Reports Added
[A recurrent PJA1 variant in trigonocephaly and neurodevelopmental disorders2020]
10/1/2019
4S
icon
3S

Decreased from 4S to 3S

New Scoring Scheme
Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module. Sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism; this finding was further validated by exome sequencing of an independent cohort of 505 ASD cases and 491 controls (Li et al., 2014). All three non-synonymous variants in ANKS1B described in this study had GERP++ conservation scores > 3.31; furthermore, of the three variants, one variant was not reported in 1000 Genomes (as of Jan/ Feb. 2013) or in SNP, while a second was not reported in 1000 Genomes, but was reported in dbSNP. Carbonell et al., 2019 described individuals with heterozygous monogenic deletions affecting the ANKS1B gene who presented with a spectrum of neurodevelopmental phenotypes, including ASD, ADHD, and developmental delay, as well as dysmorphic features; in the same report, the authors demonstrated that a transgenic mouse model of Anks1b haploinsufficiency recapitulated a range of patient phenotypes, including social deficits, hyperactivity, and sensorimotor dysfunction.

Reports Added
[Meta-Analyses Support Previous and Novel Autism Candidate Genes: Outcomes of an Unexplored Brazilian Cohort.2019] [New Scoring Scheme]
7/1/2019
4
icon
4S

Decreased from 4 to 4S

Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module. Sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism; this finding was further validated by exome sequencing of an independent cohort of 505 ASD cases and 491 controls (Li et al., 2014). All three non-synonymous variants in ANKS1B described in this study had GERP++ conservation scores > 3.31; furthermore, of the three variants, one variant was not reported in 1000 Genomes (as of Jan/ Feb. 2013) or in SNP, while a second was not reported in 1000 Genomes, but was reported in dbSNP. Carbonell et al., 2019 described individuals with heterozygous monogenic deletions affecting the ANKS1B gene who presented with a spectrum of neurodevelopmental phenotypes, including ASD, ADHD, and developmental delay, as well as dysmorphic features; in the same report, the authors demonstrated that a transgenic mouse model of Anks1b haploinsufficiency recapitulated a range of patient phenotypes, including social deficits, hyperactivity, and sensorimotor dysfunction.

Reports Added
[Haploinsufficiency in the ANKS1B gene encoding AIDA-1 leads to a neurodevelopmental syndrome.2019]
10/1/2018
icon
4

Increased from to 4

Description

This gene was originally identified as an ASD candidate gene based on its enrichment in an autism-associated protein interaction module. Sequencing of post-mortem brain tissue from 25 ASD cases resulted in the identification of significant non-synonymous variants in this gene with an expected false-positive rate at 0.1, confirming the involvement of this module with autism; this finding was further validated by exome sequencing of an independent cohort of 505 ASD cases and 491 controls (Li et al., 2014). All three non-synonymous variants in ANKS1B described in this study had GERP++ conservation scores > 3.31; furthermore, of the three variants, one variant was not reported in 1000 Genomes (as of Jan/ Feb. 2013) or in SNP, while a second was not reported in 1000 Genomes, but was reported in dbSNP.

Krishnan Probability Score

Score 0.5181840229832

Ranking 1720/25841 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 0.99277166777812

Ranking 1672/18225 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
Sanders TADA Score

Score 0.95020095931128

Ranking 18398/18665 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 0.41003753357697

Ranking 1347/20870 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
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