ANKRD11

protein-coding

ankyrin repeat domain containing 11, the group of Ankyrin repeat domain containing

Gene summary

This locus encodes an ankryin repeat domain-containing protein. The encoded protein inhibits ligand-dependent activation of transcription. Mutations in this gene have been associated with KBG syndrome, which is characterized by macrodontia, distinctive craniofacial features, short stature, skeletal anomalies, global developmental delay, seizures and intellectual disability. Alternatively spliced transcript variants have been described. Related pseudogenes exist on chromosomes 2 and X. [provided by RefSeq, Jan 2012]

MANE transcript

NM_013275.6

Inheritance

ClinVar variants

P:771U:1356B:1230

Top phenotype

KBG syndrome

gnomAD constraint

pLI —, LoF o/e 0.05

Max pathogenic AF

—

Genomic locus

chr16:89,267,619-89,490,561

External References & Databases

Ensembl (ENSG00000167522)

Transcript & Mutation Effects

hg38 • Region Span ~222.9 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

KBG syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007846

Submitter: PanelApp Australia

congenital heart defects, multiple typesLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0000119

Submitter: Ambry Genetics

KBG syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007846

Submitter: Illumina

KBG syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007846

Submitter: Orphanet

KBG syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007846

Submitter: Ambry Genetics

KBG syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007846

Submitter: G2P

KBG syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007846

Submitter: ClinGen

ANKRD11 was reported in relation to autosomal dominant KBG syndrome as early as 2011 (Sirmaci et al., PMID: 21782149). KBG syndrome is characterized by phenotypes including neurological involvement, characteristic facial dysmorphisms, macrodontia, short stature, and hand anomalies. Evidence supporting this gene-disease relationship includes case-level data and experimental data. More than 100 affected individuals have been described in the literature; however, only 9 probands (across 8 publications: 21782149, 25543316, 30088855, 27900361, 27605097, 25424714, 25464108, 28449295) are documented here, as these probands are enough to maximize the genetic evidence score in this rubric. Eight of these probands presented with mild to moderate intellectual disability, two had formal diagnoses of autism spectrum disorder, and 1 additional proband displayed autistic behavior. Six probands had developmental delay ranging from mild to severe; however, it is possible that not all patients were evaluated for this phenotype. While the majority of cases of KBG syndrome occur de novo, variants in ANKRD11 segregated with disease in 8 additional individuals in 3 of these families (PMID: 21782149, 25424714, 25464108). The proposed mechanism of disease is dominant-negative (Walz et al. 2015, PMID: 25413698). This gene-disease association is supported by animal models, expression studies, and in vitro functional assays. In summary, ANKRD11 is definitely associated with autosomal dominant KBG syndrome.

KBG syndromeSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007846

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

KBG syndromeAD

Manifestation: Craniofacial; Dental; Musculoskeletal; 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: 15523620; 15378538; 21782149; 22307766; 25125236

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ANKRD11 variants in ClinVar

50 Conditions Cataloged

KBG syndromeTotal: 2274

not providedTotal: 1266

Inborn genetic diseasesTotal: 928

not specifiedTotal: 571

ANKRD11-related disorderTotal: 337

Intellectual disabilityTotal: 39

Global developmental delayTotal: 19

Isolated dental anomaliesTotal: 17

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_013275.6. 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			10 clinvar	780 clinvar	19 clinvar	809
missense	7 clinvar	40 clinvar	1334 clinvar	409 clinvar	22 clinvar	1812
nonsense	143 clinvar	75 clinvar	3 clinvar			221
start loss						0
frameshift	309 clinvar	169 clinvar	4 clinvar			482
splice donor/acceptor (+/-2bp)	16 clinvar	12 clinvar	5 clinvar			33
Total	475	296	1356	1189	41	3357

Highest pathogenic variant AF is 0.000012392787

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 70 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_013275.6	RefSeq	NP_037407.4	11	MANE Select
ENST00000301030.10	Ensembl	ENSP00000301030.4	11	MANE Select
NM_001256182.2	RefSeq	NP_001243111.1	11	Standard
NM_001256183.2	RefSeq	NP_001243112.1	11	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

in utero embryonic development
tissue homeostasis
multicellular organism growth
odontogenesis of dentin-containing tooth
skeletal system morphogenesis

Cellular Component

nucleus
nucleoplasm
cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000301030
Coding exons: 11
Length: 222932
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	-0.554	1657	1.59e+3	1.04	0.000114	17483
Missense (PolyPhen)		463	660.5	0.70098		7316
Synonymous	-7.96	1033	755	1.37	0.0000660	5171
Loss of Function	8.17	4	85.5	0.0468	0.00000496	1133

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0.000029	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000098	0.000092	rare
European (Non-Finnish)	0.000037	0.000035	rare
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Chromatin regulator which modulates histone acetylation and gene expression in neural precursor cells (By similarity). May recruit histone deacetylases (HDACs) to the p160 coactivators/nuclear receptor complex to inhibit ligand-dependent transactivation (PubMed:15184363). Has a role in proliferation and development of cortical neural precursors (PubMed:25556659). May also regulate bone homeostasis (By similarity). {ECO:0000250|UniProtKB:E9Q4F7, ECO:0000269|PubMed:15184363, ECO:0000269|PubMed:25556659}.;
Disease: DISEASE: KBG syndrome (KBGS) [MIM:148050]: A syndrome characterized by macrodontia of the upper central incisors, distinctive craniofacial findings, short stature, skeletal anomalies, and neurologic involvement that includes global developmental delay, seizures, and intellectual disability. {ECO:0000269|PubMed:21782149, ECO:0000269|PubMed:25413698}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.107

Intolerance Scores

LoFtool: 0.0131
RVIS EVS: -4.38
RVIS percentile EVS: 0.09

Essentials

Essential (CRISPR): E
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.934

Gene Damage Prediction

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