ANK2
protein-codingankyrin 2, the group of Ankyrin repeat domain containing|MicroRNA protein coding host genes|Cilia and flagella associated
Gene summary
This gene encodes a member of the ankyrin family of proteins that link the integral membrane proteins to the underlying spectrin-actin cytoskeleton. Ankyrins play key roles in activities such as cell motility, activation, proliferation, contact and the maintenance of specialized membrane domains. Most ankyrins are typically composed of three structural domains: an amino-terminal domain containing multiple ankyrin repeats; a central region with a highly conserved spectrin binding domain; and a carboxy-terminal regulatory domain which is the least conserved and subject to variation. The protein encoded by this gene is required for targeting and stability of Na/Ca exchanger 1 in cardiomyocytes. Mutations in this gene cause long QT syndrome 4 and cardiac arrhythmia syndrome. Multiple transcript variants encoding different isoforms have been described. [provided by RefSeq, Dec 2011]
- LQT4
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~566.2 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AD
Disease ID:MONDO:0017990
Submitter: ClinGen
ANK2 was evaluated for autosomal dominant catecholaminergic polymorphic ventricular tachycardia (CPVT). ANK2, which encodes the ankyrin B protein, has been implicated in a number of arrhythmia phenotypes but has been classified as Disputed for both Brugada syndrome and Long QT syndrome by the respective Gene Curation Expert Panels. Variants in ANK2 have been detected in 3 patients/families with CPVT-like symptoms (Mohler et al, 2004, PMID:15178757; Mohler et al, 2007, PMID:17242276). However the population frequencies of these variants are too high to be an autosomal dominant cause of CPVT – p.Leu1622Ile (gnomAD max MAF = 0.034), p.Arg1788Trp (gnomAD max MAF = 0.002) and p.Val1516Asp (gnomAD max MAF = 0.004). AnkB heterozygous null mice have been shown to display exercise and epinephrine-induced polymorphic ventricular arrhythmias before death (Mohler et al, 2003, PMID:12571597). While this phenotype can be rescued with transfection of wild type ankyrin-B, mutant ankyrin-B with the human arrhythmia-associated variants described above (and variants associated with other arrhythmias) were unable to rescue this phenotype (Mohler et al, 2004, PMID:15178757; Mohler et al, 2007, PMID:17242276). Nevertheless, despite this experimental evidence, there is no convincing human genetic evidence to associate ANK2 as an autosomal dominant cause of CPVT and therefore this gene has been classified as Disputed. Note: All CPVT genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the CPVT Gene Curation Expert Panel (GCEP). The classification and summary presented here is the conclusion of this GCEP's analysis according to evidence teams' efforts. This classification was approved by the ClinGen Catecholaminergic Polymorphic Ventricular Tachycardia Gene Curation Expert Panel on 20th January, 2021 (SOP Version 7).
Inheritance Pattern: AD
Disease ID:MONDO:0002442
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0700092
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0015263
Submitter: ClinGen
Inheritance Pattern: AD
Disease ID:MONDO:0010958
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: Ambry Genetics
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: ClinGen
*ANK2* was first reported in relation to autosomal dominant complex neurodevelopmental disorder in 2012 (Iossifov et al., PMID: 22542183). Individuals with variants in this gene have presented with neurodevelopmental phenotypes including autism spectrum disorder, intellectual disability, seizures, and microcephaly. Seven *de novo* protein truncating variants (frameshift and nonsense) that have been reported in 8 probands in 7 publications (PMIDs: 22542183, 25363768, 27479843, 28554332, 30564305, 30755392, 31981491) are included in this curation. More evidence is available in the literature (PMIDs: 25363760, 27824329, 28191889, 28263302, 33004838, 33057194), but the maximum score for genetic evidence (12 points) has been reached. One *de novo* missense variant (PMID: 25621899) with evidence of loss-of-function (PMID: 31285321) and at least six *de novo* missense variants of unknown significance (PMIDs: 28135719, 31981491) have also been reported in individuals with neurodevelopmental disorders. The mechanism of pathogenicity is predicted to be loss-of-function based on the protein truncating variants reported in individuals affected with neurodevelopmental disorders and experimental data showing reduced protein expression in cultured cells bearing truncating variants in *ANK2* (PMID: 31285321). The gene-disease association is also supported by mouse models and rescue experiments in cultured cells (PMID: 31285321). Of note, loss-of-function missense variants in *ANK2* have also been observed in individuals with long QT syndrome (PMIDs: 15178757, 17242276); the ClinGen Long QT Gene Curation Expert Panel is evaluating the clinical validity of this reported gene-disease relationship. In summary, there is definitive evidence supporting the relationship between *ANK2* and autosomal dominant complex neurodevelopmental disorder. This classification was approved by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 21, 2020 (SOP Version 7).
Inheritance Pattern: AD
Disease ID:MONDO:0002442
Submitter: ClinGen
ANK2 encodes Ankyrin2, a protein important for localization and membrane stabilization of cardiac ion channels. This gene is located within a very large (~16 million bp) region identified by linkage analysis in a large family with LQTS (PMID 7485162). Subsequent sequencing of ANK2 in members of this family identified a missense variant (p.Glu1458Gly) that at time of publication (2003, PMID 12571597) was thought to be pathogenic. Contemporary data, however, demonstrates this variant has a population frequency too high for an autosomal dominant cause of LQTS (~1:400 individuals of Latino ancestry). Due to lack of other segregation data or case-control data and paucity of additional genetic and experimental data, this gene-disease association was classified as disputed. Note: All LQTS genes were curated by 3 separate blinded teams. The evidence and scores reached by these 3 teams was reviewed by the LQTS Clinical Domain Working Group. The classification and summary presented here is the conclusion of this Working Group's analysis according to evidence available at time of publication. The scores presented here are the result of only one of the three curation teams' efforts. For a detailed discussion of this group's work and the scores of all 3 teams please see "Adler et al. An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. Circulation 2020;141(6):418-428. doi: 10.1161/CIRCULATIONAHA.119.043132”
Inheritance Pattern: AD
Disease ID:MONDO:0017990
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0000992
Submitter: Genomics England PanelApp
Inheritance Pattern: Unknown
Disease ID:MONDO:0010958
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AD
Disease ID:MONDO:0010958
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0015263
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0100038
Submitter: PanelApp Australia
Inheritance Pattern: AD
Disease ID:MONDO:0015263
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0017990
Submitter: Genomics England PanelApp
Clinical Genomic Database (CGD)
Manifestation: Cardiovascular
Intervention: Cardiovascular
Rationale: Individuals may present with a variety of manifestations depending on the type of arrhythmia, including stress/exercise-induced arrhythmias, syncope, and sudden cardiac death, and surveillance (eg, with electrocardiogram) and medical (eg, including ICD placement) management may be effective to prevent severe sequelae of cardiac arrhythmias
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to ANK2 variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_001148.6. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 19 | 1034 | 15 | 1069 | |
| missense | 1 | 15 | 2082 | 374 | 11 | 2483 |
| nonsense | 21 | 18 | 12 | 51 | ||
| start loss | 1 | 1 | ||||
| frameshift | 24 | 12 | 13 | 1 | 50 | |
| splice donor/acceptor (+/-2bp) | 2 | 11 | 11 | 24 | ||
| Total | 48 | 57 | 2138 | 1409 | 26 | 3678 |
Highest pathogenic variant AF is 0.000020452839
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_001139.3 | 46 | MANE Select | |
| Ensembl | ENSP00000349588.4 | 46 | MANE Select | |
| RefSeq | NP_001120965.1 | 46 | Standard | |
| RefSeq | NP_001341154.1 | 47 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Proteoglycans in cancer - Homo sapiens (human)
- Antiarrhythmic Pathway, Pharmacodynamics
- Developmental Biology
- Vesicle-mediated transport
- Membrane Trafficking
Biological Process
- regulation of heart rate
- atrial septum development
- cellular calcium ion homeostasis
- endoplasmic reticulum to Golgi vesicle-mediated transport
- endocytosis
Molecular Function
- structural constituent of cytoskeleton
- protein binding
- enzyme binding
- protein kinase binding
- spectrin binding
Cellular Component
- mitochondrion
- lysosome
- early endosome
- cytosol
- cytoskeleton
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000357077
- Coding exons
- 46
- Length
- 565632
- Individuals with no LoFs
- 125717
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 31
- Defined
- 125748
- p
- 0.000123
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 1.96 | 1812 | 2.06e+3 | 0.878 | 0.000113 | 25877 |
| Missense (PolyPhen) | 659 | 946.99 | 0.69589 | 11858 | ||
| Synonymous | -0.570 | 806 | 786 | 1.03 | 0.0000461 | 7932 |
| Loss of Function | 11.0 | 10 | 160 | 0.0626 | 0.00000943 | 2025 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.000062 | 0.000062 | rare |
| Latino/Admixed American | 0.000087 | 0.000087 | rare |
| Ashkenazi Jewish | 0.000099 | 0.000099 | rare |
| East Asian | 0.000054 | 0.000054 | rare |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.00013 | 0.00012 | rare |
| South Asian | 0.00033 | 0.00033 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: In skeletal muscle, required for proper localization of DMD and DCTN4 and for the formation and/or stability of a special subset of microtubules associated with costameres and neuromuscular junctions. Attaches integral membrane proteins to cytoskeletal elements. Also binds to cytoskeletal proteins. Required for coordinate assembly of Na/Ca exchanger, Na/K ATPase and InsP3 receptor at sarcoplasmic reticulum sites in cardiomyocytes. Required for the coordinated expression of the Na/K ATPase, Na/Ca exchanger and beta-2-spectrin (SPTBN1) in the inner segment of rod photoreceptors (By similarity). Required for expression and targeting of SPTBN1 in neonatal cardiomyocytes and for the regulation of neonatal cardiomyocyte contraction rate (PubMed:12571597). Plays a role in endocytosis and intracellular protein transport. Associates with phosphatidylinositol 3- phosphate (PI3P)-positive organelles and binds dynactin to promote long-range motility of cells. Recruits RABGAP1L to (PI3P)-positive early endosomes, where RABGAP1L inactivates RAB22A, and promotes polarized trafficking to the leading edge of the migrating cells. Part of the ANK2/RABGAP1L complex which is required for the polarized recycling of fibronectin receptor ITGA5 ITGB1 to the plasma membrane that enables continuous directional cell migration (By similarity). {ECO:0000250|UniProtKB:Q8C8R3, ECO:0000269|PubMed:12571597}.;
- Disease
- DISEASE: Long QT syndrome 4 (LQT4) [MIM:600919]: A heart disorder characterized by a prolonged QT interval on the ECG and polymorphic ventricular arrhythmias. They cause syncope and sudden death in response to exercise or emotional stress, and can present with a sentinel event of sudden cardiac death in infancy. Long QT syndrome type 4 shows many atypical features compared to classical long QT syndromes, including pronounced sinus bradycardia, polyphasic T waves and atrial fibrillation. Cardiac repolarization defects may be not as severe as in classical LQT syndromes and prolonged QT interval on EKG is not a consistent feature. {ECO:0000269|PubMed:12571597, ECO:0000269|PubMed:15178757}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.132
Intolerance Scores
- LoFtool
- 0.363
- RVIS EVS
- -3.33
- RVIS percentile EVS
- 0.41
Essentials
- Essential (CRISPR)
- N
- Essential (CRISPR2)
- N
- Essential (gene trap)
- N
- Indispensability pred.
- E
- Indispensability score
- 0.632
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | High | Medium | High |
| Cancer | High | High | High |