Human Gene Module / Chromosome 4 / ANK2

ANK2Ankyrin 2, neuronal

Score
1
High Confidence Criteria 1.1
Autism Reports / Total Reports
10 / 11
Rare Variants / Common Variants
64 / 0
Aliases
ANK2, ANK-2,  LQT4,  brank-2
Associated Syndromes
-
Genetic Category
Rare Single Gene Mutation
Chromosome Band
4q25-q26
Associated Disorders
-
Relevance to Autism

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

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.

Reports related to ANK2 (11 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 De novo genic mutations among a Chinese autism spectrum disorder cohort. Wang T , et al. (2016) Yes -
10 Support Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. C Yuen RK , et al. (2017) Yes -
11 Support Genomic diagnosis for children with intellectual disability and/or developmental delay. Bowling KM , et al. (2017) Yes -
Rare Variants   (64)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.2683C>T p.Arg895Ter stop_gained De novo - Simplex 22542183 Iossifov I , et al. (2012)
c.11717G>A p.Arg3906Gln missense_variant Familial Maternal Multiplex 23999528 Toma C , et al. (2013)
c.2968C>T p.Arg990Ter stop_gained De novo - Simplex 24267886 Willsey AJ , et al. (2013)
c.3262C>T p.Arg1088Ter stop_gained De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.2421C>G p.Ile807Met missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
c.4139C>G p.Pro1380Arg missense_variant De novo - Simplex 25363760 De Rubeis S , et al. (2014)
del(T) - frameshift_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.310C>T p.Arg104Ter stop_gained Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.899G>A p.Arg300Gln missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3173G>A p.Arg1058Gln missense_variant Familial Maternal Multiplex 25363760 De Rubeis S , et al. (2014)
c.3670G>A p.Val1224Ile missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.853G>A p.Asp285Asn missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4592T>A p.Leu1522Gln missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.4837G>A p.Asp1613Asn 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.10062A>C p.Arg3354Ser missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.2998T>C p.Ser1000Pro missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3001T>C p.Ser1001Pro missense_variant Familial Maternal 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.9086A>G p.Glu3029Gly missense_variant Familial Paternal Simplex 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.1073G>T p.Arg358Leu missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.3971C>T p.Leu1324Phe missense_variant Familial Paternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5159C>T p.Ala1720Val missense_variant Familial Maternal Simplex 25363760 De Rubeis S , et al. (2014)
c.5552C>T p.Ser1851Leu missense_variant Familial Maternal (n=1), paternal (n=1) Simplex 25363760 De Rubeis S , et al. (2014)
c.2500C>T p.Arg834Ter 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 - splice_site_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3034A>C p.Ser1012Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4049C>T p.Thr1350Met missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4294G>T p.Ala1432Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.4483C>T p.Arg1495Trp missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6535G>A p.Gly2179Ser missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.883A>C p.Ile295Leu missense_variant 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.5243G>A p.Arg1748Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.166G>A p.Val56Met 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.2104G>A p.Ala702Thr missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3011G>A p.Gly1004Ala missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3092C>A p.Pro1031Gln missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.3959A>G p.Lys1320Arg missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
c.6542C>T p.Pro2181Leu 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.2945G>A p.Arg982Gln 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.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.11807A>G p.Tyr3936Cys missense_variant Unknown - Unknown 25363760 De Rubeis S , et al. (2014)
p.7326delG p.Arg2609fs frameshift_variant De novo - Simplex 25363768 Iossifov I , et al. (2014)
c.3320A>G p.Glu1107Gly missense_variant De novo - Unknown 25533962 Deciphering Developmental Disorders Study (2014)
c.10286A>T p.Glu3429Val missense_variant De novo - Multiplex 25621899 Yuen RK , et al. (2015)
c.5530C>T p.Pro1844Ser missense_variant De novo - Simplex 25961944 Krumm N , et al. (2015)
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.8797del p.Ser2933ProfsTer40 frameshift_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.11650G>A p.Glu3884Lys missense_variant Unknown Not maternal - 27824329 Wang T , et al. (2016)
c.11683G>A p.Val3895Met missense_variant Familial Paternal - 27824329 Wang T , et al. (2016)
c.9055A>G p.Met3019Val missense_variant De novo - Simplex 28263302 C Yuen RK , et al. (2017)
c.5207C>G p.Ser1736Ter stop_gained Unknown - Multiplex 28263302 C Yuen RK , et al. (2017)
c.4764delT p.Gln1589Lysfs frameshift_variant De novo - - 28554332 Bowling KM , et al. (2017)
Common Variants  

No common variants reported.

SFARI Gene score
1

High Confidence

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).

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.

04-01-2017
1

Initial score established: 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).

CNVs associated with ANK2(1 CNVs)
4q25-q26 4 Duplication 6  /  4
Animal Models associated with ANK2(2 Models)
Ank2_1_KO_HM Genetic
Ank2_1_KO_HT Genetic
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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