ANK3

protein-coding

ankyrin 3, the group of Ankyrin repeat domain containing

Gene summary

Ankyrins are a family of proteins that are believed to link the integral membrane proteins to the underlying spectrin-actin cytoskeleton and play key roles in activities such as cell motility, activation, proliferation, contact, and the maintenance of specialized membrane domains. Multiple isoforms of ankyrin with different affinities for various target proteins are expressed in a tissue-specific, developmentally regulated manner. 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. Ankyrin 3 is an immunologically distinct gene product from ankyrins 1 and 2, and was originally found at the axonal initial segment and nodes of Ranvier of neurons in the central and peripheral nervous systems. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2011]

MANE transcript

NM_020987.5

Inheritance

AR, SD, AD

ClinVar variants

P:35U:1190B:502

Top phenotype

Intellectual developmental disorder, autosomal recessive 37

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr10:60,026,298-60,733,490

External References & Databases

Ensembl (ENSG00000151150)

Transcript & Mutation Effects

hg38 • Region Span ~707.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

intellectual disabilityMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0001071

Submitter: ClinGen

The *ANK3* gene encodes a member of the ankyrin family, which anchors membrane proteins to the underlying spectrin-actin cytoskeleton. Brain-specific isoforms of ANK3 are localized at the nodes of Ranvier and the axon initial segment and are involved in the clustering of voltage-gated ion channels required for the generation and propagation of action potentials. *ANK3* was first reported in relation to autosomal recessive intellectual disability in 2013 (Iqbal et al., PMID: 23390136). Clinical findings include developmental delay, intellectual disability, behavioral problems, seizures, and brain imaging abnormalities. Heterozygous *ANK3* variants have also been reported in individuals with neurodevelopmental disorders. Per criteria outlined by the ClinGen Lumping and Splitting guidelines, we found differences in molecular mechanism, inheritance pattern and phenotypic variability. Therefore, the curation was split by inheritance pattern. This curation focuses on the relationship between *ANK3* and autosomal recessive intellectual disability. The split curation for autosomal dominant complex neurodevelopmental disorder has been curated separately. Three homozygous frameshift variants in this gene have been reported in six affected individuals from three families in three publications (PMIDs: 23390136, 29302074, 32404165). In addition, ten homozygous or compound heterozygous missense variants, most lacking functional evidence of pathogenicity, have been reported in seven families (PMIDs: 26539891, 31451636, 3677705, 38988293). *ANK3* is highly constrained both for loss-of-function and missense variants. The mechanism of pathogenicity is biallelic loss of function, which has been suggested to be isoform-specific. *ANK3* encodes three major isoforms: the widely expressed 190 kDa isoform, and the 270 and 480 kDa isoforms, which are primarily expressed in the brain. Recessive variants affect the giant exon domain, which is present only in the longest, 480 kDa isoform, whereas dominant truncating variants are located in the N-terminal domain and disrupt all three transcripts (PMIDs: 34218362, 38988293). Individuals with biallelic variants exhibit a more severe phenotype than those with monoallelic variants (PMID: 38988293). This gene-disease relationship is also supported by experimental evidence, including animal models in mice (PMID: 25552556) and Drosophila (PMIDs: 18439406, 23390136). In summary, there is moderate evidence supporting the relationship between *ANK3* and autosomal recessive intellectual disability. While more evidence is needed to establish this relationship definitively, no convincing contradictory evidence has emerged. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism Gene Curation Expert Panel on October 7, 2020. It was reevaluated on October 2, 2024 (SOP Version 11). Although additional families were curated, only one had biallelic loss-of-function variants (PMID: 32404165), and the classification did not change.

neurodevelopmental disorderSTRONG

Inheritance Pattern: SD

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

colobomaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0001476

Submitter: PanelApp Australia

intellectual developmental disorder, autosomal recessive 37SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014210

Submitter: Orphanet

Tourette syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0007661

Submitter: Labcorp Genetics (formerly Invitae)

intellectual developmental disorder, autosomal recessive 37LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014210

Submitter: Ambry Genetics

intellectual developmental disorder, autosomal recessive 37STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014210

Submitter: Labcorp Genetics (formerly Invitae)

intellectual disabilityLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0001071

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Intellectual developmental disorder, autosomal recessive 37AR

Manifestation: Neurologic

Intervention: General

Rationale: 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

Refs: 23390136; 29302074

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ANK3 variants in ClinVar

16 Conditions Cataloged

not providedTotal: 1385

Inborn genetic diseasesTotal: 515

not specifiedTotal: 201

Intellectual disability-hypotonia-spasticity-sleep disorder syndromeTotal: 117

ANK3-related disorderTotal: 100

Intellectual disabilityTotal: 9

Neurodevelopmental disorderTotal: 3

See casesTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020987.5. 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			20 clinvar	374 clinvar	13 clinvar	407
missense		5 clinvar	1144 clinvar	106 clinvar	9 clinvar	1264
nonsense	4 clinvar	7 clinvar	9 clinvar			20
start loss						0
frameshift	10 clinvar	5 clinvar	12 clinvar			27
splice donor/acceptor (+/-2bp)	1 clinvar	3 clinvar	5 clinvar			9
Total	15	20	1190	480	22	1727

Highest pathogenic variant AF is 0.000009913271

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 39 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020987.5	RefSeq	NP_066267.2	43	MANE Select
ENST00000280772.7	Ensembl	ENSP00000280772.1	43	MANE Select
NM_001149.4	RefSeq	NP_001140.2	20	Standard
NM_001204403.2	RefSeq	NP_001191332.1	43	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Proteoglycans in cancer - Homo sapiens (human)
Splicing factor NOVA regulated synaptic proteins
Developmental Biology
Vesicle-mediated transport
Membrane Trafficking

Biological Process

mitotic cytokinesis
endoplasmic reticulum to Golgi vesicle-mediated transport
plasma membrane organization
cytoskeletal anchoring at plasma membrane
signal transduction

Molecular Function

structural constituent of cytoskeleton
protein binding
cytoskeletal protein binding
spectrin binding
protein binding, bridging

Cellular Component

lysosome
endoplasmic reticulum
Golgi apparatus
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000280772
Coding exons: 43
Length: 707193
Individuals with no LoFs: 125731
Homozygous LoFs: 0
Heterozygous LoFs: 17
Defined: 125748
p: 0.0000676

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.79	1928	2.31e+3	0.836	0.000126	28644
Missense (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

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000087	0.000058	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00016	0.00016	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.000080	0.000079	rare
South Asian	0.000033	0.000033	rare
Other	0.00017	0.00016	rare

dbNSFP Gene Annotations

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}.;

Recessive Scores

pRec: 0.229

Intolerance Scores

LoFtool: 0.202
RVIS EVS: -3.5
RVIS percentile EVS: 0.34

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.842

Gene Damage Prediction

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