ANKRD17

protein-coding

ankyrin repeat domain 17, the group of Ankyrin repeat domain containing

Gene summary

The protein encoded by this gene belongs to the family of ankyrin repeat-containing proteins, and contains two distinct arrays of ankyrin repeats in its amino-terminal region, one with 15 ankyrin repeats, and the other with 10 ankyrin repeats. It also contains a nuclear export signal, nuclear localization signal, and a cyclin-binding RXL motif. Localization of this protein to the nucleus has been shown experimentally, and interactions between this protein and cyclin-dependent kinase 2 have been observed. It has been suggested that this protein plays a role in both DNA replication and in both anti-viral and anti-bacterial innate immune pathways. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Dec 2015]

MANE transcript

NM_032217.5

Inheritance

ClinVar variants

P:55U:496B:67

Top phenotype

Chopra-Amiel-Gordan syndrome

gnomAD constraint

pLI —, LoF o/e 0.02

Max pathogenic AF

—

Genomic locus

chr4:73,073,376-73,258,798

External References & Databases

Ensembl (ENSG00000132466)

Transcript & Mutation Effects

hg38 • Region Span ~185.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Chopra-Amiel-Gordon syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859186

Submitter: G2P

syndromic complex neurodevelopmental disorderDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800439

Submitter: ClinGen

*ANKRD17* is an ankyrin repeat domain-containing protein implicated in cell cycle progression, immune regulation , and cell growth, differentiation, proliferation, and migration through the Yorkie/Hippo/YAP pathway. *ANKRD17* was first reported in relation to autosomal dominant syndromic complex neurodevelopmental disorder, also known as Chopra-Amiel-Gordon Syndrome (CAGS) (OMIM:619504), in 2021 (Chopra et al., PMID: 33909992). Pathogenic variants in *ANKRD17* cause a syndromic neurodevelopmental disorder characterized by intellectual disability/developmental delay particularly affecting speech and facial dysmorphism. Additional features may include growth deficiency, feeding difficulties, ophthalmological abnormalities, gait/balances disturbances, recurrent infections, autism and epilepsy. The disease entity has been curated under syndromic complex neurodevelopmental disorder. The proposed mechanism is heterozygous loss of function, supported by the mutational spectrum and the intolerance to variation in the general population. Evidence supporting this gene-disease relationship includes case-level data. Ten variants (3 nonsense variants, 2 frameshift variants, 3 missense variants, and 1 essential splice site variant) that have been reported in 11 probands in one publication (PMID: 33909992) are included in this curation. Of these 11 probands, one had a variant that was inherited from an affected parent (not counted as a proband) and the remaining 10 probands had *de novo* variants, including one proband with a variant shared with her monozygous twin (not counted as a proband). More case-level evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. Individuals with atypical phenotypes harboring missense ANKRD17 variants, , including one case reported by Silverstein et al. (PMID: 36277850) with an intracranial hemorrhage, and one case in the Brain Gene Registry with severe hypertension have been noted. The significance of these reports is unclear. The homozygous mouse model is embryonic lethal due to failure of vascular development (Hou et al., 2009, PMID: 19619540), so brain and behavior is not able to be studied in this model system. In summary, there is definitive evidence to support the relationship between *ANKRD17* and autosomal dominant syndromic complex neurodevelopmental disorder. This gene-disease pair was originally evaluated by the ClinGen Intellectual Disability and Autism GCEP on March 9, 2023. It was reevaluated on December 12, 2024. As a result of this reevaluation, the classification increased from Strong to Definitive because three years have elapsed. No new evidence has been reviewed or added.

Chopra-Amiel-Gordon syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859186

Submitter: Labcorp Genetics (formerly Invitae)

Chopra-Amiel-Gordon syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0859186

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Chopra-Amiel-Gordan syndromeAD

Manifestation: Allergy/Immunology/Infectious; Craniofacial; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Allergy/Immunology/Infectious

Rationale: Among other findings, the condition may involve susceptibility to infections, and awareness may allow preventative measures and early and aggressive treatment of infections

Refs: 33909992

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ANKRD17 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 256

Inborn genetic diseasesTotal: 231

Chopra-Amiel-Gordon syndromeTotal: 93

ANKRD17-related disorderTotal: 42

not specifiedTotal: 40

See casesTotal: 2

Hereditary sensory neuropathy-deafness-dementia syndromeTotal: 1

Neurodevelopmental delayTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_032217.5. 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			8 clinvar	29 clinvar	6 clinvar	43
missense		15 clinvar	474 clinvar	30 clinvar	2 clinvar	521
nonsense	4 clinvar	8 clinvar	1 clinvar			13
start loss						0
frameshift	15 clinvar	11 clinvar	2 clinvar			28
splice donor/acceptor (+/-2bp)	2 clinvar		11 clinvar			13
Total	21	34	496	59	8	618

Highest pathogenic variant AF is 0.0000038216017

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 52 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_032217.5	RefSeq	NP_115593.3	34	MANE Select
ENST00000358602.9	Ensembl	ENSP00000351416.4	34	MANE Select
NM_001286771.3	RefSeq	NP_001273700.1	34	Standard
NM_015574.2	RefSeq	NP_056389.1	34	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

blood vessel maturation
regulation of DNA replication
viral process
defense response to bacterium
positive regulation of I-kappaB kinase/NF-kappaB signaling

Molecular Function

chromatin binding
RNA binding
protein binding

Cellular Component

chromatin
nucleus
cytoplasm
membrane
nuclear membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000358602
Coding exons: 34
Length: 185423
Individuals with no LoFs: 125741
Homozygous LoFs: 0
Heterozygous LoFs: 7
Defined: 125748
p: 0.0000278

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	5.36	802	1.36e+3	0.591	0.0000678	16805
Missense (PolyPhen)		97	300.9	0.32237		3523
Synonymous	0.181	490	495	0.990	0.0000260	5421
Loss of Function	9.13	2	101	0.0198	0.00000516	1312

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00018	0.00016	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000027	0.000026	rare
South Asian	0	0.0	absent
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Could play pivotal roles in cell cycle and DNA regulation (PubMed:19150984). Involved in innate immune defense against viruse by positively regulating the viral dsRNA receptors DDX58 and IFIH1 signaling pathways (PubMed:22328336). Involves in NOD2- and NOD1-mediated responses to bacteria suggesting a role in innate antibacterial immune pathways too (PubMed:23711367). Target of enterovirus 71 which is the major etiological agent of HFMD (hand, foot and mouth disease) (PubMed:17276651). Could play a central role for the formation and/or maintenance of the blood vessels of the circulation system (By similarity). {ECO:0000250|UniProtKB:Q99NH0, ECO:0000269|PubMed:17276651, ECO:0000269|PubMed:19150984, ECO:0000269|PubMed:22328336, ECO:0000269|PubMed:23711367}.;

Intolerance Scores

LoFtool: 0.0262
RVIS EVS: -2.94
RVIS percentile EVS: 0.55

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.819

Gene Damage Prediction

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