ANK2

ankyrin 2, the group of Ankyrin repeat domain containing|MicroRNA protein coding host genes|Cilia and flagella associated

Basic information

Region (hg38): 4:112818032-113384221

Previous symbols: [ "LQT4" ]

Links

ENSG00000145362 ∙ NCBI:287 ∙ OMIM:106410 ∙ HGNC:493 ∙ Uniprot:Q01484 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• catecholaminergic polymorphic ventricular tachycardia (Limited), mode of inheritance: AD
• Brugada syndrome (Limited), mode of inheritance: AD
• heart conduction disease (Limited), mode of inheritance: AD
• cardiac arrhythmia, ankyrin-B-related (Strong), mode of inheritance: AD
• cardiac arrhythmia, ankyrin-B-related (Limited), mode of inheritance: Unknown
• Brugada syndrome (Disputed Evidence), mode of inheritance: AD
• complex neurodevelopmental disorder (Definitive), mode of inheritance: AD
• catecholaminergic polymorphic ventricular tachycardia (Disputed Evidence), mode of inheritance: AD
• long QT syndrome (Disputed Evidence), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Long QT syndrome, 4; Cardiac arrhythmia, ankyrin-B-related	AD	Cardiovascular	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	Cardiovascular	7485162; 12571597; 15178757; 17242276; 17940615; 18790697; 18832177; 20809527; 21859974

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ANK2 gene.

• Cardiovascular phenotype (6 variants)
• not provided (3 variants)
• ANK2-associated Neurodevelopmental Disorder (2 variants)
• Cardiac arrhythmia, ankyrin-B-related (1 variants)
• Autism spectrum disorder (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ANK2 gene is commonly pathogenic or not.

In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.

Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.

Variant type	Pathogenic	Likely pathogenic	VUS	Likely benign	Benign	Sum
synonymous			15	712	26	753
missense		1	1425	120	10	1556
nonsense	7	6	9			22
start loss						0
frameshift	5	7	13	1		26
inframe indel			11	2		13
splice donor/acceptor (+/-2bp)		2	7			9
splice region			36	52	5	93
non coding		1	34	213	102	350
Total	12	17	1514	1048	138

Highest pathogenic variant AF is 0.00000657

Variants in ANK2

This is a list of pathogenic ClinVar variants found in the ANK2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-112904252-T-C			Benign (Jun 16, 2018)
4-112904455-G-C			Benign (Mar 01, 2022)
4-112904538-A-G			Likely benign (Aug 17, 2018)
4-112904566-G-A			Likely benign (Jul 17, 2018)
4-112904665-A-T			Benign (Jun 14, 2018)
4-112904713-T-C			Benign (Jun 19, 2018)
4-113049340-G-C			Likely benign (Jul 15, 2018)
4-113049603-C-T			Benign (Mar 03, 2015)
4-113049622-A-C			Benign (Mar 03, 2015)
4-113049690-G-T		not specified • Cardiac arrhythmia, ankyrin-B-related	Conflicting classifications of pathogenicity (Jan 13, 2018)
4-113049711-C-G		not specified	Benign (Jul 07, 2015)
4-113049732-A-G		Cardiovascular phenotype	Uncertain significance (Aug 13, 2021)
4-113049734-G-A		Long QT syndrome	Uncertain significance (Jul 07, 2023)
4-113049741-G-T			Uncertain significance (Aug 07, 2024)
4-113049757-G-A		Autism spectrum disorder	Likely benign (Jul 28, 2022)
4-113049760-A-T		Cardiovascular phenotype	Uncertain significance (May 22, 2019)
4-113049763-G-T			Uncertain significance (Apr 05, 2021)
4-113049764-T-C		Long QT syndrome	Likely benign (Oct 18, 2022)
4-113049765-G-T		Meniere disease	Uncertain significance (Jun 03, 2024)
4-113049770-G-T		Long QT syndrome	Uncertain significance (Apr 09, 2022)
4-113049776-C-G		Cardiovascular phenotype	Uncertain significance (Jul 28, 2023)
4-113049776-C-T		Cardiovascular phenotype • Long QT syndrome	Likely benign (Mar 14, 2022)
4-113049777-A-G		Cardiovascular phenotype • Meniere disease	Uncertain significance (Sep 18, 2023)
4-113049784-G-A		Cardiac arrhythmia, ankyrin-B-related • Long QT syndrome • Cardiovascular phenotype	Conflicting classifications of pathogenicity (Apr 20, 2023)
4-113049791-G-A		Long QT syndrome • Cardiovascular phenotype	Likely benign (Apr 19, 2024)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ANK2	protein_coding	protein_coding	ENST00000357077	46	565632

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	2.86e-19	125717	0	31	125748	0.000123

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	1.96	1812	2.06e+3	0.878	0.000113	25877
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000148	0.000148
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.0000544	0.0000544
Finnish	0.00	0.00
European (Non-Finnish)	0.000133	0.000123
Middle Eastern	0.0000544	0.0000544
South Asian	0.000327	0.000327
Other	0.000163	0.000163

dbNSFP

Source: dbNSFP

• 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.
• Pathway: Proteoglycans in cancer - Homo sapiens (human);Antiarrhythmic Pathway, Pharmacodynamics;Developmental Biology;Vesicle-mediated transport;Membrane Trafficking;Post-translational protein modification;Metabolism of proteins;Transport to the Golgi and subsequent modification;Asparagine N-linked glycosylation;Interaction between L1 and Ankyrins;L1CAM interactions;COPI-mediated anterograde transport;Axon guidance;ER to Golgi Anterograde Transport (Consensus)

Recessive Scores

• pRec: 0.132

Intolerance Scores

• loftool: 0.363
• rvis_EVS: -3.33
• rvis_percentile_EVS: 0.41

Haploinsufficiency Scores

• pHI: 0.965
• hipred: Y
• hipred_score: 0.705
• ghis: 0.599

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.632

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	High	Medium	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Ank2
• Phenotype: nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); vision/eye phenotype; liver/biliary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span); endocrine/exocrine gland phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); muscle phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype

Gene ontology

• Biological process: regulation of heart rate;atrial septum development;cellular calcium ion homeostasis;endoplasmic reticulum to Golgi vesicle-mediated transport;endocytosis;cytoskeleton organization;positive regulation of gene expression;regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion;regulation of cardiac muscle contraction by calcium ion signaling;protein transport;paranodal junction assembly;regulation of protein stability;T-tubule organization;protein localization to organelle;protein localization to cell surface;cellular protein localization;protein localization to M-band;protein localization to T-tubule;positive regulation of potassium ion transport;protein stabilization;regulation of release of sequestered calcium ion into cytosol;response to methylmercury;regulation of calcium ion transport;positive regulation of calcium ion transport;regulation of cardiac muscle contraction;regulation of ventricular cardiac muscle cell membrane repolarization;sarcoplasmic reticulum calcium ion transport;protein localization to endoplasmic reticulum;protein localization to plasma membrane;regulation of cardiac muscle cell contraction;ventricular cardiac muscle cell action potential;atrial cardiac muscle cell action potential;SA node cell action potential;membrane depolarization during SA node cell action potential;atrial cardiac muscle cell to AV node cell communication;SA node cell to atrial cardiac muscle cell communication;regulation of heart rate by cardiac conduction;regulation of SA node cell action potential;regulation of atrial cardiac muscle cell action potential;positive regulation of potassium ion transmembrane transporter activity;regulation of calcium ion transmembrane transporter activity;positive regulation of calcium ion transmembrane transporter activity;positive regulation of cation channel activity
• Cellular component: mitochondrion;lysosome;early endosome;cytosol;cytoskeleton;plasma membrane;intercalated disc;membrane;basolateral plasma membrane;apical plasma membrane;Z disc;T-tubule;M band;A band;sarcolemma;costamere;axon initial segment;membrane raft;postsynaptic membrane;recycling endosome
• Molecular function: structural constituent of cytoskeleton;protein binding;enzyme binding;protein kinase binding;spectrin binding;protein binding, bridging;ion channel binding;ATPase binding;phosphorylation-dependent protein binding