ANK3

ankyrin 3, the group of Ankyrin repeat domain containing

Basic information

Region (hg38): 10:60026297-60733490

Links

ENSG00000151150 ∙ NCBI:288 ∙ OMIM:600465 ∙ HGNC:494 ∙ Uniprot:Q12955 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• Tourette syndrome (Limited), mode of inheritance: Unknown
• intellectual disability-hypotonia-spasticity-sleep disorder syndrome (Limited), mode of inheritance: AR
• intellectual disability-hypotonia-spasticity-sleep disorder syndrome (Supportive), mode of inheritance: AR
• intellectual disability (Limited), mode of inheritance: AD
• intellectual disability-hypotonia-spasticity-sleep disorder syndrome (Strong), mode of inheritance: AR
• intellectual disability (Moderate), mode of inheritance: AR

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Intellectual developmental disorder, autosomal recessive 37	AR	General	Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing	Neurologic	23390136; 29302074

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ANK3 gene.

• not provided (841 variants)
• not specified (157 variants)
• Inborn genetic diseases (150 variants)
• Intellectual disability-hypotonia-spasticity-sleep disorder syndrome (93 variants)
• ANK3-related condition (5 variants)
• Intellectual disability (3 variants)
• ANK3-related neurodevelopmental disorder (2 variants)
• See cases (2 variants)
• Intellectual disability, autosomal recessive 66 (2 variants)
• Global developmental delay (1 variants)
• Abnormal brain morphology (1 variants)
• Classic medulloblastoma (1 variants)
• ANK3-related disorder (1 variants)
• Autism (1 variants)
• Abnormality of the nervous system (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ANK3 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			12	247	26	285
missense		1	535	29	12	577
nonsense	1	2	2			5
start loss						0
frameshift	5	5	3			13
inframe indel			11			11
splice donor/acceptor (+/-2bp)			1			1
splice region			12	15	8	35
non coding			4	53	18	75
Total	6	8	568	329	56

Highest pathogenic variant AF is 0.00000658

Variants in ANK3

This is a list of pathogenic ClinVar variants found in the ANK3 region.

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

Position	Type	Phenotype	Significance	ClinVar
10-60042584-C-A		Intellectual disability-hypotonia-spasticity-sleep disorder syndrome	Benign (Jul 14, 2021)
10-60042595-A-T		Intellectual disability-hypotonia-spasticity-sleep disorder syndrome	Benign (Jul 14, 2021)
10-60042616-A-T		Intellectual disability-hypotonia-spasticity-sleep disorder syndrome	Benign (Jul 14, 2021)
10-60042617-A-T		Intellectual disability-hypotonia-spasticity-sleep disorder syndrome	Benign (Jul 14, 2021)
10-60042682-C-A		not specified	Uncertain significance (Nov 19, 2015)
10-60042682-C-G		not specified	Uncertain significance (Nov 19, 2015)
10-60042695-G-A		Intellectual disability-hypotonia-spasticity-sleep disorder syndrome	Uncertain significance (Oct 03, 2023)
10-60042716-T-A		Inborn genetic diseases • ANK3-related disorder	Conflicting classifications of pathogenicity (Jan 04, 2024)
10-60042718-C-T			Likely benign (Jun 26, 2023)
10-60042719-C-T		not specified • Intellectual disability-hypotonia-spasticity-sleep disorder syndrome • ANK3-related disorder	Benign/Likely benign (Mar 01, 2024)
10-60042720-G-A			Uncertain significance (Jul 17, 2022)
10-60042739-C-T		not specified	Uncertain significance (Dec 08, 2016)
10-60042743-T-A			Uncertain significance (Nov 01, 2020)
10-60042771-G-A			Benign (Jun 09, 2023)
10-60042792-A-T		Intellectual disability-hypotonia-spasticity-sleep disorder syndrome	Benign (Jul 14, 2021)
10-60042803-G-T		Intellectual disability-hypotonia-spasticity-sleep disorder syndrome	Benign (Jul 14, 2021)
10-60042819-T-TC		Intellectual disability-hypotonia-spasticity-sleep disorder syndrome	Benign (Jul 14, 2021)
10-60055638-C-T			Benign/Likely benign (Dec 07, 2023)
10-60055639-G-A			Likely benign (Nov 22, 2022)
10-60055646-C-A			Likely benign (Aug 04, 2023)
10-60055682-C-G		Inborn genetic diseases	Uncertain significance (Apr 07, 2023)
10-60055686-T-C		Inborn genetic diseases	Uncertain significance (Jan 10, 2022)
10-60055693-G-A			Uncertain significance (Dec 02, 2021)
10-60055697-G-T		not specified • Inborn genetic diseases	Conflicting classifications of pathogenicity (Jan 16, 2024)
10-60055699-T-G		Intellectual disability-hypotonia-spasticity-sleep disorder syndrome	Uncertain significance (Nov 18, 2021)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ANK3	protein_coding	protein_coding	ENST00000280772	43	707193

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
1.00	4.25e-21	125731	0	17	125748	0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.79	1928	2.31e+3	0.836	0.000126	28644
Missense in Polyphen		751	1121.2	0.66981		13862
Synonymous	-0.661	909	884	1.03	0.0000523	8708
Loss of Function	11.2	8	162	0.0493	0.00000853	2211

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.0000870	0.0000870
Ashkenazi Jewish	0.00	0.00
East Asian	0.000163	0.000163
Finnish	0.0000463	0.0000462
European (Non-Finnish)	0.0000797	0.0000791
Middle Eastern	0.000163	0.000163
South Asian	0.0000329	0.0000327
Other	0.000166	0.000163

dbNSFP

Source: dbNSFP

• Function: FUNCTION: In skeletal muscle, required for costamere localization of DMD and betaDAG1 (By similarity). Membrane-cytoskeleton linker. May participate in the maintenance/targeting of ion channels and cell adhesion molecules at the nodes of Ranvier and axonal initial segments. Regulates KCNA1 channel activity in function of dietary Mg(2+) levels, and thereby contributes to the regulation of renal Mg(2+) reabsorption (PubMed:23903368). {ECO:0000250, ECO:0000269|PubMed:17974005}.
• Disease: DISEASE: Note=Genetic variations in ANK3 may be associated with autism spectrum disorders susceptibility. {ECO:0000269|PubMed:22865819}.; DISEASE: Mental retardation, autosomal recessive 37 (MRT37) [MIM:615493]: A disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT37 patients manifest delayed global development with speech delay, hypotonia, spasticity, and a sleep disorder. Severe behavioral abnormalities include aggression, hyperactivity, and grinding of the teeth. Note=The disease is caused by mutations affecting the gene represented in this entry. A homozygous deletion in ANK3 predicted to result in frameshift and premature truncation, has been shown to be the cause of moderate intellectual disability, an ADHD-like phenotype and behavioral problems in a consanguineous family (PubMed:23390136). {ECO:0000269|PubMed:23390136}.
• Pathway: Proteoglycans in cancer - Homo sapiens (human);Splicing factor NOVA regulated synaptic proteins;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: 0.229

Intolerance Scores

• loftool: 0.202
• rvis_EVS: -3.5
• rvis_percentile_EVS: 0.34

Haploinsufficiency Scores

• pHI: 0.858
• hipred: Y
• hipred_score: 0.585
• ghis: 0.610

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.842

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Ank3
• 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); renal/urinary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); respiratory system phenotype; 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)

Gene ontology

• Biological process: mitotic cytokinesis;endoplasmic reticulum to Golgi vesicle-mediated transport;plasma membrane organization;cytoskeletal anchoring at plasma membrane;signal transduction;axonogenesis;neuromuscular junction development;positive regulation of gene expression;positive regulation of cell communication by electrical coupling;positive regulation of sodium ion transport;magnesium ion homeostasis;neuronal action potential;positive regulation of homotypic cell-cell adhesion;Golgi to plasma membrane protein transport;regulation of potassium ion transport;establishment of protein localization;positive regulation of membrane potential;cellular response to magnesium ion;membrane assembly;protein localization to plasma membrane;maintenance of protein location in plasma membrane;positive regulation of protein targeting to membrane;protein localization to axon;positive regulation of membrane depolarization during cardiac muscle cell action potential;negative regulation of delayed rectifier potassium channel activity;positive regulation of sodium ion transmembrane transporter activity;positive regulation of cation channel activity
• Cellular component: lysosome;endoplasmic reticulum;Golgi apparatus;cytosol;plasma membrane;bicellular tight junction;basal plasma membrane;cell surface;intercalated disc;spectrin-associated cytoskeleton;membrane;basolateral plasma membrane;lateral plasma membrane;sarcoplasmic reticulum;Z disc;T-tubule;dendrite;neuromuscular junction;node of Ranvier;sarcolemma;neuron projection;costamere;axon initial segment;postsynaptic membrane
• Molecular function: structural constituent of cytoskeleton;protein binding;cytoskeletal protein binding;spectrin binding;protein binding, bridging;ion channel binding;cadherin binding