Human Gene Module / Chromosome 11 / AHNAK

AHNAKAHNAKnucleoprotein

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
6 / 6
Rare Variants / Common Variants
50 / 0
Aliases
AHNAK, AHNAKRS,  PM227
Associated Syndromes
-
Chromosome Band
11q12.3
Associated Disorders
DD/NDD, ID
Relevance to Autism

De novo missense variants in AHNAK have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014), the Simons Simplex Collection (Iossifov et al., 2014; Turner et al., 2017), and the SPARK cohort (Wang et al., 2020). Single-molecular molecular inversion probe (smMIP) sequencing of 3,363 probands from cohorts with a primary diagnosis of ASD in Wang et al., 2020 identified 15 ASD-associated likely gene-disruptive (LGD) variants and 9 ASD-associated missense variants with CADD scores 30 in the AHNAK gene.

Molecular Function

The protein encoded by this gene is a large (700 kDa) structural scaffold protein consisting of a central domain with 128 aa repeats. The encoded protein may play a role in such diverse processes as blood-brain barrier formation, cell structure and migration, cardiac calcium channel regulation, and tumor metastasis. A much shorter variant encoding a 17 kDa isoform exists for this gene, and the shorter isoform initiates a feedback loop that regulates alternative splicing of this gene.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to AHNAK (6 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support 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 Support Genomic Patterns of De Novo Mutation in Simplex Autism Turner TN et al. (2017) Yes -
4 Primary Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes DD, ID
5 Support - Alonso-Gonzalez A et al. (2021) Yes -
6 Support - Zhou X et al. (2022) Yes -
Rare Variants   (50)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.154+1G>T - splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.2508T>G p.Tyr836Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.9437G>A p.Trp3146Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.10G>A p.Glu4Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.23G>A p.Arg8Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.17239A>T p.Lys5747Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.17398G>T p.Glu5800Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.17581C>T p.Arg5861Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.200C>T p.Ser67Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.262C>T p.Arg88Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.263G>T p.Arg88Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.346G>A p.Gly116Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.394C>T p.Arg132Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.276C>T p.Arg92%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.7948G>T p.Gly2650Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3956A>G p.Lys1319Arg missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.13639G>A p.Asp4547Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.15587T>C p.Ile5196Thr missense_variant De novo - - 33004838 Wang T et al. (2020)
c.17335C>T p.Arg5779Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.17336G>A p.Arg5779His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.14986C>T p.Leu4996%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.16158C>T p.Ser5386%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.3658G>A p.Val1220Ile splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.9638A>C p.Asn3213Thr splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.15577C>T p.Gln5193Ter stop_gained Familial Maternal - 33004838 Wang T et al. (2020)
c.15772C>T p.Gln5258Ter stop_gained Familial Paternal - 33004838 Wang T et al. (2020)
c.262C>T p.Arg88Cys missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.4804C>T p.Pro1602Ser missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.682del p.Ala228ProfsTer24 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.2784del p.Lys928AsnfsTer2 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.15879dup p.Met5294TyrfsTer8 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.17126dup p.Ser5710ValfsTer9 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.422C>G p.Ser141Ter stop_gained Familial Paternal Simplex 33004838 Wang T et al. (2020)
c.7977T>C p.Asp2659%3D synonymous_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.15410del p.Lys5137ArgfsTer19 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.17307del p.Leu5770TyrfsTer51 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.7701A>C p.Leu2567Phe missense_variant De novo - Simplex 28965761 Turner TN et al. (2017)
c.8079dup p.Lys2694Ter frameshift_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.15880A>G p.Met5294Val frameshift_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.16165G>A p.Ala5389Thr missense_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.17089_17102del p.Asp5697ArgfsTer3 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.16311_16321del p.Val5438ProfsTer14 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.13580del p.Asn4527IlefsTer2 frameshift_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.4500G>T p.Glu1500Asp missense_variant De novo - Simplex 33431980 Alonso-Gonzalez A et al. (2021)
c.16311_16323delinsAA p.Val5438ThrfsTer14 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.7784_7787delinsTGT p.Gly2595ValfsTer42 splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.16811_16812del p.Ser5604CysfsTer8 frameshift_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.17094_17095del p.Glu5699ValfsTer5 frameshift_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.17094_17095del p.Glu5699ValfsTer5 frameshift_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.3812_3813insGGGCC p.Arg1272GlyfsTer7 frameshift_variant Unknown - Simplex 33004838 Wang T et al. (2020)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

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.

4/1/2022
icon
2

Increased from to 2

Krishnan Probability Score

Score 0.32984304395286

Ranking 24920/25841 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 0.34456738710666

Ranking 6258/18225 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 0.87013293683992

Ranking 4309/18665 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 0.095447476141071

Ranking 6232/20870 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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