Human Gene Module / Chromosome 4 / ANK2

ANK2Ankyrin 2, neuronal

SFARI Gene Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
30 / 35
Rare Variants / Common Variants
190 / 0
EAGLE Score
10.8
Moderate Learn More
Aliases
ANK2, ANK-2,  LQT4,  brank-2
Associated Syndromes
-
Chromosome Band
4q25-q26
Associated Disorders
ID
Genetic Category
Rare Single Gene Mutation, Functional
Relevance to Autism

A total of three de novo loss-of-function (LoF) variants in the ANK2 gene have been identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 24267886, 25363768), while a fourth de novo LoF in this gene was identified in an ASD proband from the Autism Sequencing Consortium in De Rubeis et al., 2014 (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) in De Rubeis et al., 2014 identified ANK2 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified ANK2 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene encodes a member of the ankyrin family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton. This gene is associated with Long QT syndrome 4 (LQT4) [MIM:600919], a heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
Mouse
Entrez GeneMouse Genome Informatics
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to ANK2 (35 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 Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism Willsey AJ , et al. (2013) Yes -
3 Recent Recommendation Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
4 Support The contribution of de novo coding mutations to autism spectrum disorder Iossifov I et al. (2014) Yes -
5 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
6 Support Whole-genome sequencing of quartet families with autism spectrum disorder Yuen RK , et al. (2015) Yes -
7 Support Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
8 Recent Recommendation Low load for disruptive mutations in autism genes and their biased transmission Iossifov I , et al. (2015) Yes -
9 Support Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci Sanders SJ , et al. (2015) Yes -
10 Support De novo genic mutations among a Chinese autism spectrum disorder cohort Wang T , et al. (2016) Yes -
11 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder C Yuen RK et al. (2017) Yes -
12 Support Genomic diagnosis for children with intellectual disability and/or developmental delay Bowling KM , et al. (2017) Yes -
13 Support Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders Li J , et al. (2017) Yes -
14 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
15 Support Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes Feliciano P et al. (2019) Yes -
16 Support Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism Satterstrom FK et al. (2020) Yes -
17 Support Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use Husson T , et al. (2020) Yes -
18 Support Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
19 Support - Mahjani B et al. (2021) Yes -
20 Support - Creighton BA et al. (2021) Yes -
21 Support - Kawano S et al. (2022) Yes -
22 Support - Zhou X et al. (2022) Yes -
23 Support - Chen Y et al. (2022) No -
24 Support - Yuan B et al. (2023) Yes -
25 Recent Recommendation - Pintacuda G et al. (2023) Yes -
26 Support - Guissart C et al. (2023) Yes -
27 Recent Recommendation - Teunissen MWA et al. (2023) No ASD, ADHD
28 Support - Oh H et al. (2023) Yes -
29 Support - Wang J et al. (2023) Yes -
30 Support - Yoon S et al. (2023) Yes -
31 Support - Cirnigliaro M et al. (2023) Yes -
32 Support - Murphy KE et al. (2023) No -
33 Support - Omri Bar et al. (2024) Yes ADHD, BPD, OCD, ID, learning disability
34 Recent Recommendation - Andrew D Nelson et al. (2024) Yes -
35 Support - Axel Schmidt et al. (2024) No -
Rare Variants   (190)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.*35C>T - stop_gained Unknown - - 33004838 Wang T et al. (2020)
- - copy_number_loss De novo - - 37195288 Teunissen MWA et al. (2023)
- - copy_number_loss Unknown - - 37195288 Teunissen MWA et al. (2023)
c.4400-4143C>T - stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.4400-4494G>T - stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.*76A>T - stop_gained Familial Paternal - 33004838 Wang T et al. (2020)
c.4399+4113C>T - missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4399+4175C>T - missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4400-2349G>A - missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4400-3032G>A - missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4400-3033C>T - missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4400-3059G>A - missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4400-3311C>T - missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2941C>T p.Arg981Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.3103C>T p.Pro1035Ser stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.4252C>T p.Arg1418Ter stop_gained Unknown - - 33004838 Wang T et al. (2020)
c.6055C>T p.Gln2019Ter stop_gained De novo - - 35982159 Zhou X et al. (2022)
c.4399+3148del - frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.4399+4052del - frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.1288-5C>T - splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.2799-1G>A - splice_site_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.257G>A p.Arg86Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.688C>A p.Leu230Ile missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.899G>A p.Arg300Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1268C>T p.Ser423Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1297G>A p.Gly433Arg missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1448C>T p.Ala483Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1514C>T p.Ala505Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1552C>T p.Arg518Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1774C>A p.Leu592Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1831C>T p.Pro611Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1871C>T p.Ala624Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1943C>T p.Ala648Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1991C>T p.Thr664Ile missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2006C>T p.Ala669Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2203G>A p.Ala735Thr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2773C>T p.Arg925Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2918G>A p.Arg973Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2942G>A p.Arg981Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2959C>T p.Arg987Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1517G>A p.Arg506His missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.3005G>A p.Arg1002His missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3083G>A p.Ser1028Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3163G>A p.Glu1055Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3265C>T p.Arg1089Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3545G>A p.Arg1182Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3550C>A p.Arg1184Ser missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3886C>G p.Arg1296Gly missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3914C>T p.Ala1305Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3989C>T p.Pro1330Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4180T>A p.Phe1394Ile missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4247G>T p.Cys1416Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4426G>A p.Glu1476Lys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4625G>A p.Cys1542Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5401G>A p.Val1801Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5434C>T p.Arg1812Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.5543G>C p.Arg1848Pro missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.8894C>T p.Thr2965Ile missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.4399+3133del - frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
c.862C>T p.His288Tyr stop_gained De novo - - 37195288 Teunissen MWA et al. (2023)
c.922C>T p.Gln308Ter stop_gained De novo - - 37195288 Teunissen MWA et al. (2023)
c.1288-1G>A - splice_site_variant De novo - - 37195288 Teunissen MWA et al. (2023)
c.2179-1G>A - splice_site_variant De novo - - 37195288 Teunissen MWA et al. (2023)
c.2797-1G>A - splice_site_variant De novo - - 37195288 Teunissen MWA et al. (2023)
c.10798C>G p.Gln3600Glu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.11800G>A p.Asp3934Asn missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.11266A>T p.Lys3756Ter missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.2121del p.Val708Ter frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.4400-1560C>T - missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.4400-2349G>A - missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.4400-3032G>T - missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.4400-4206G>A - missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.3007C>T p.Arg1003Ter stop_gained De novo - Simplex 30564305 Guo H , et al. (2018)
c.3019C>T p.Arg1007Ter stop_gained De novo - - 37195288 Teunissen MWA et al. (2023)
c.4400-4986del - frameshift_variant De novo - - 37195288 Teunissen MWA et al. (2023)
c.10463del p.Leu3488Ter frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.222+1G>T - splice_site_variant De novo - Simplex 37088467 Guissart C et al. (2023)
c.10768G>T p.Glu3590Ter stop_gained De novo - - 37195288 Teunissen MWA et al. (2023)
c.4400-3319del - frameshift_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.4400-1628_4400-1627dup - frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.4240G>A p.Glu1414Lys splice_region_variant De novo - - 35982159 Zhou X et al. (2022)
c.679G>A p.Val227Met missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.9184G>T p.Glu3062Ter stop_gained De novo - Simplex 32094338 Husson T , et al. (2020)
c.3339C>T p.Asn1113= synonymous_variant De novo - - 31452935 Feliciano P et al. (2019)
c.5329G>C p.Val1777Leu missense_variant De novo - Simplex 28831199 Li J , et al. (2017)
c.1247T>G p.Leu416Arg missense_variant Unknown - Simplex 33004838 Wang T et al. (2020)
c.2683C>T p.Arg895Ter stop_gained De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.2968C>T p.Arg990Ter stop_gained De novo - Simplex 24267886 Willsey AJ , et al. (2013)
c.4371G>A p.Lys1457= synonymous_variant De novo - - 39039281 Axel Schmidt et al. (2024)
c.4399+2924G>T - missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4399+3113C>T - missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4399+5003G>A - missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4399+5010C>T - missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3198-1G>A - splice_site_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.7999G>A p.Glu2667Lys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.9173G>T p.Arg3058Leu missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.9856G>A p.Glu3286Lys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.814G>A p.Asp272Asn missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.898C>T p.Arg300Trp missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.5207C>G p.Ser1736Ter stop_gained Unknown - Multiplex 28263302 C Yuen RK et al. (2017)
c.2599C>T p.Arg867Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2944C>T p.Arg982Ter stop_gained Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
G>A p.Asn3521Tyr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.10645C>T p.Arg3549Cys missense_variant Familial - Simplex 28831199 Li J , et al. (2017)
c.1205C>T p.Ser402Leu missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.2000T>A p.Ile667Asn missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.2000T>A p.Ile667Asn missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.2218G>C p.Gly740Arg missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.4038del p.Trp1347GlyfsTer2 frameshift_variant De novo - - 35982159 Zhou X et al. (2022)
c.3262C>T p.Arg1088Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.3865A>T p.Arg1289Trp missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.4243C>A p.Pro1415Thr missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.5351C>A p.Pro1784His missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.5368G>A p.Glu1790Lys missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.5434C>T p.Arg1812Trp missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.5434C>T p.Arg1812Trp missense_variant Familial Paternal - 33004838 Wang T et al. (2020)
c.5683del p.Ser1895LeufsTer99 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.5412+2T>C - splice_site_variant Familial Paternal Simplex 33004838 Wang T et al. (2020)
c.1118C>T p.Ala373Val missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.2930G>A p.Arg977Gln missense_variant Familial Maternal - 27824329 Wang T , et al. (2016)
c.5530C>T p.Pro1844Ser missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
c.9055A>G p.Met3019Val missense_variant De novo - Simplex 28263302 C Yuen RK et al. (2017)
c.166G>A p.Asp56Asn missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.11683G>A p.Val3895Met missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.883A>C p.Lys295Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.899G>A p.Arg300Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4123_4125del p.Ala1375del inframe_deletion De novo - Simplex 37393044 Wang J et al. (2023)
c.10286A>T p.Glu3429Val missense_variant De novo - Multiplex 25621899 Yuen RK , et al. (2015)
c.2421C>G p.Ile807Met missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2104G>A p.Ala702Thr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.2945G>A p.Arg982Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1961_1967del p.Thr654ArgfsTer32 frameshift_variant De novo - - 33004838 Wang T et al. (2020)
c.4139C>G p.Pro1380Arg missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.3047G>A p.Gly1016Asp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3128C>A p.Pro1043Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3268A>C p.Ser1090Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3539A>G p.Gln1180Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3959A>G p.Glu1320Gly missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4049C>T p.Thr1350Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5243G>A p.Arg1748Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.5392G>A p.Gly1798Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.7228G>C p.Glu2410Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.9284C>T p.Thr3095Ile missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.9298C>A p.Pro3100Thr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.11650G>A p.Glu3884Lys missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.11807A>G p.Tyr3936Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.1088T>G p.Leu363Arg missense_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.4112C>T XP_005262998.1:p.Pro1371Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.3934_3937del p.Ile1312SerfsTer10 splice_site_variant De novo - - 36881370 Yuan B et al. (2023)
c.1103C>G p.Ala368Gly missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.1574C>T p.Ala525Val missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.2455G>A p.Glu819Lys missense_variant Familial Paternal Simplex 30564305 Guo H , et al. (2018)
c.4399+3627C>T - missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4399+3921C>T - missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4400-2044A>C - missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4400-2382G>A - missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4293G>A p.Leu1431= synonymous_variant De novo - Simplex 31981491 Satterstrom FK et al. (2020)
c.11241_11245del p.Glu3747AspfsTer14 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.2620C>T p.Arg874Ter stop_gained Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.11003_11006del p.Glu3668GlyfsTer106 frameshift_variant Unknown - - 33004838 Wang T et al. (2020)
c.11650G>A p.Glu3884Lys missense_variant Familial Maternal Simplex 30564305 Guo H , et al. (2018)
c.4399+5075del - frameshift_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.7826del p.Asp2610TfsTer23 frameshift_variant De novo - Simplex 25363768 Iossifov I et al. (2014)
c.11717G>A p.Arg3906Gln missense_variant Familial Maternal Multiplex 23999528 Toma C , et al. (2013)
c.6311G>C p.Ser2104Thr missense_variant Familial Maternal Multiplex 38256266 Omri Bar et al. (2024)
c.899G>A p.Arg300Gln missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1046_1047del p.His349ArgfsTer91 frameshift_variant De novo - - 37195288 Teunissen MWA et al. (2023)
c.5479C>T p.Gln1827Ter stop_gained Familial Paternal Multiplex 37506195 Cirnigliaro M et al. (2023)
c.1073G>T p.Arg358Leu missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1315A>G p.Thr439Ala missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.1912T>A p.Thr638Ala missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3632_3633del p.Ile1211ArgfsTer40 frameshift_variant De novo - - 37195288 Teunissen MWA et al. (2023)
c.6853_6857del p.Ile2285TrpfsTer4 frameshift_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.8797del p.Ser2933ProfsTer40 frameshift_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.3904G>A p.Val1302Ile missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4204C>T p.Leu1402Phe missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4565T>A p.Leu1522Gln missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4837G>A p.Glu1613Lys missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5173G>A p.Glu1725Lys missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5243G>A p.Arg1748Gln missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5443T>C p.Ser1815Pro missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5446T>C p.Ser1816Pro missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5552C>T p.Thr1851Ile missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.9086A>G p.Gln3029Arg missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.9952G>A XP_005262998.1:p.Glu3318Lys missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.3173G>A p.Ser1058Asn missense_variant Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.4579C>G p.Leu1527Val missense_variant Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.10804G>A XP_005262998.1:p.Glu3602Lys missense_variant Familial Maternal - 33004838 Wang T et al. (2020)
c.3065G>A XP_005262998.1:p.Arg1022Gln missense_variant Unknown Not paternal - 33004838 Wang T et al. (2020)
c.3320A>G p.Glu1107Gly missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

Score Delta: Score remained at 1

criteria met
See SFARI Gene'scoring criteria
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.

10/1/2020
1
icon
1

Score remained at 1

Description

A total of three de novo LoF variants in the ANK2 gene have been identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 24267886, 25363768), while a fourth de novo LoF in this gene was identified in an ASD proband from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ANK2 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
1/1/2020
1
icon
1

Score remained at 1

Description

A total of three de novo LoF variants in the ANK2 gene have been identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 24267886, 25363768), while a fourth de novo LoF in this gene was identified in an ASD proband from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ANK2 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Insights into Autism Spectrum Disorder Genomic Architecture and Biology from 71 Risk Loci.2015] [Large-Scale Exome Sequencing Study Implicates Both Developmental and Functional Changes in the Neurobiology of Autism2020] [Rare genetic susceptibility variants assessment in autism spectrum disorder: detection rate and practical use.2020]
10/1/2019
1
icon
1

Score remained at 1

New Scoring Scheme
Description

A total of three de novo LoF variants in the ANK2 gene have been identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 24267886, 25363768), while a fourth de novo LoF in this gene was identified in an ASD proband from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ANK2 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes2019] [New Scoring Scheme]
1/1/2019
1
icon
1

Score remained at 1

Description

A total of three de novo LoF variants in the ANK2 gene have been identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 24267886, 25363768), while a fourth de novo LoF in this gene was identified in an ASD proband from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ANK2 as a gene meeting high statistical significance with a FDR 0.01, meaning that this gene had a 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model.2018]
10/1/2017
1
icon
1

Score remained at 1

Description

A total of three de novo LoF variants in the ANK2 gene have been identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 24267886, 25363768), while a fourth de novo LoF in this gene was identified in an ASD proband from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ANK2 as a gene meeting high statistical significance with a FDR ? 0.01, meaning that this gene had a ? 99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[Targeted sequencing and functional analysis reveal brain-size-related genes and their networks in autism spectrum disorders.2017]
4/1/2017
1
icon
1

Score remained at 1

Description

A total of three de novo LoF variants in the ANK2 gene have been identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 24267886, 25363768), while a fourth de novo LoF in this gene was recently identified in an ASD proband from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ANK2 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015] [De novo genic mutations among a Chinese autism spectrum disorder cohort.2016] [Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder2017] [Genomic diagnosis for children with intellectual disability and/or developmental delay.2017]
10/1/2016
1
icon
1

Score remained at 1

Description

A total of three de novo LoF variants in the ANK2 gene have been identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 24267886, 25363768), while a fourth de novo LoF in this gene was recently identified in an ASD proband from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ANK2 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

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

Score remained at 1

Description

A total of three de novo LoF variants in the ANK2 gene have been identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 24267886, 25363768), while a fourth de novo LoF in this gene was recently identified in an ASD proband from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ANK2 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760). This gene was identified in Iossifov et al. 2015 as a strong candidate to be an ASD risk gene based on a combination of de novo mutational evidence and the absence or very low frequency of mutations in controls (PMID 26401017).

Reports Added
[De novo gene disruptions in children on the autistic spectrum.2012] [Coexpression networks implicate human midfetal deep cortical projection neurons in the pathogenesis of autism.2013] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014] [Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Excess of rare, inherited truncating mutations in autism.2015] [Low load for disruptive mutations in autism genes and their biased transmission.2015]
4/1/2015
1
icon
1

Score remained at 1

Description

A total of three de novo LoF variants in the ANK2 gene have been identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 24267886, 25363768), while a fourth de novo LoF in this gene was recently identified in an ASD proband from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ANK2 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

Reports Added
[Excess of rare, inherited truncating mutations in autism.2015]
1/1/2015
1
icon
1

Score remained at 1

Description

A total of three de novo LoF variants in the ANK2 gene have been identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 24267886, 25363768), while a fourth de novo LoF in this gene was recently identified in an ASD proband from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ANK2 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

Reports Added
[Whole-genome sequencing of quartet families with autism spectrum disorder.2015] [Large-scale discovery of novel genetic causes of developmental disorders.2014]
10/1/2014
3
icon
1

Decreased from 3 to 1

Description

A total of three de novo LoF variants in the ANK2 gene have been identified in ASD probands from the Simons Simplex Collection (PMIDs 22542183, 24267886, 25363768), while a fourth de novo LoF in this gene was recently identified in an ASD proband from the Autism Sequencing Consortium (PMID 25363760). Analysis of rare coding variation in 3,871 ASD cases and 9,937 ancestry-matched or paternal controls from the Autism Sequencing Consortium (ASC) identified ANK2 as a gene meeting high statistical significance with a FDR ?0.01, meaning that this gene had a ?99% chance of being a true autism gene (PMID 25363760).

Reports Added
[Synaptic, transcriptional and chromatin genes disrupted in autism.2014] [The contribution of de novo coding mutations to autism spectrum disorder2014]
7/1/2014
No data
icon
3

Increased from No data to 3

Description

Two de novo LGD variants in the ANK2 gene have been identified in simplex ASD cases from the Simons Simplex Collection (Iossifov et al., 2012; Willsey et al., 2013).

4/1/2014
No data
icon
3

Increased from No data to 3

Description

Two de novo LGD variants in the ANK2 gene have been identified in simplex ASD cases from the Simons Simplex Collection (Iossifov et al., 2012; Willsey et al., 2013).

Krishnan Probability Score

Score 0.7658477418814

Ranking 9/25841 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 0.99999999999981

Ranking 30/18225 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 0.997

Ranking 11/239 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 1.3489461142824E-5

Ranking 8/18665 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
Larsen Cumulative Evidence Score

Score 106

Ranking 7/461 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.
Original Source
Zhang D Score

Score 0.21071291839134

Ranking 4097/20870 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
External PIN Data
BioGRIDHuman Protein Reference Database
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ACOT7 acyl-CoA thioesterase 7 Human Protein Binding 11332 O00154
C14ORF104 Protein kintoun Human Protein Binding 55172 Q9NVR5-2
CCT2 chaperonin containing TCP1, subunit 2 (beta) Human Protein Binding 10576 P78371
CHL1 cell adhesion molecule with homology to L1CAM (close homolog of L1) Human Protein Binding 10752 O00533
CRNKL1 crooked neck pre-mRNA splicing factor-like 1 (Drosophila) Human Protein Binding 51340 Q9BZJ0
DGUOK deoxyguanosine kinase Human Protein Binding 1716 E5KSL5
DMD dystrophin Human Protein Binding 1756 P11532
DNAJB1 DnaJ (Hsp40) homolog, subfamily B, member 1 Human Protein Binding 3337 P25685
EPB42 erythrocyte membrane protein band 4.2 Human Protein Binding 2038 P16452
FARP1 FERM, RhoGEF (ARHGEF) and pleckstrin domain protein 1 (chondrocyte-derived) Human Protein Binding 10160 Q9Y4F1
FTSJ3 FtsJ homolog 3 (E. coli) Human Protein Binding 117246 Q8IY81
HAX1 HCLS1 associated protein X-1 Human Protein Binding 10456 O00165
HIF1AN hypoxia inducible factor 1, alpha subunit inhibitor Human Protein Binding 55662 Q9NWT6
IP3R-3 inositol 1,4,5-trisphosphate receptor, type 3 Rat Protein Binding 25679 Q63269
L1CAM L1 cell adhesion molecule Rat Protein Binding 50687 Q05695
MAPK8IP1 mitogen-activated protein kinase 8 interacting protein 1 Human Protein Binding 9479 Q6NUQ9
MYO1D myosin ID Human Protein Binding 4642 O94832
NDEL1 nudE nuclear distribution E homolog (A. nidulans)-like 1 Human Protein Binding 81565 Q9GZM8
NFASC neurofascin Rat Protein Binding 116690 P97685
NRCAM neuronal cell adhesion molecule Rat Protein Binding 497815 Q6PW34
NUFIP1 Nuclear FMRP Interacting Protein 1 Human Protein Binding 26747 Q9UHK0
OBSCN obscurin, cytoskeletal calmodulin and titin-interacting RhoGEF Human Protein Binding 84033 Q5VST9
PALM2 paralemmin 2 Human Protein Binding 114299 Q8IXS6
RAPGEF5 Rap guanine nucleotide exchange factor (GEF) 5 Human Protein Binding 9771 A8MQ07
SIGMAR1 sigma non-opioid intracellular receptor 1 Rat Protein Binding 29336 Q9R0C9
SLC8A1 solute carrier family 8 (sodium/calcium exchanger), member 1 Rat Protein Binding 29715 Q01728
SNCA synuclein, alpha (non A4 component of amyloid precursor) Human Protein Binding 6622 P37840
SPTAN1 spectrin, alpha, non-erythrocytic 1 Rat Protein Binding 64159 P16086
SPTB spectrin, beta, erythrocytic Rat Protein Binding 314251 Q6XDA0
SPTBN1 spectrin, beta, non-erythrocytic 1 Human Protein Binding 6711 Q01082
TAF9 TAF9 RNA polymerase II, TATA box binding protein (TBP)-associated factor, 32kDa Human Protein Binding 6880 Q16594
TNIK TRAF2 and NCK interacting kinase Human Protein Binding 23043 Q9UKE5
TP53 tumor protein p53 Human Protein Binding 7157 P04637
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