ANKRD26

protein-coding

ankyrin repeat domain containing 26, the group of Ankyrin repeat domain containing

Gene summary

This gene encodes a protein containing N-terminal ankyrin repeats which function in protein-protein interactions. Mutations in this gene are associated with autosomal dominant thrombocytopenia-2. Pseudogenes of this gene are found on chromosome 7, 10, 13 and 16. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

Previous symbols:

THC2

MANE transcript

NM_014915.3

Inheritance

ClinVar variants

P:3U:2002B:865

Top phenotype

Thrombocytopenia 2

gnomAD constraint

pLI —, LoF o/e 0.58

Max pathogenic AF

—

Genomic locus

chr10:26,973,793-27,100,494

External References & Databases

Ensembl (ENSG00000107890)

Transcript & Mutation Effects

hg38 • Region Span ~126.7 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

thrombocytopenia 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008555

Submitter: G2P

thrombocytopenia 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008555

Submitter: Ambry Genetics

thrombocytopenia 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008555

Submitter: ClinGen

ANKRD26 was first reported in relation to autosomal dominant thrombocytopenia 2 in 2011 (Pippucci T, et al., PMID: 21211618). At least 20 unique variants (in the 5’UTR) have been reported in humans. Evidence supporting this gene disease relationship includes case-level data, segregation data, and experimental data. Variants in this gene have been reported in at least 18 probands in 7 publications (PMIDs: 26175287, 23677566, 30747248, 28109976, 24030261, 21467542, 21211618). Variants in this gene segregated with disease in 38 additional family members. The mechanism of disease is proposed to be gain of function, not haploinsufficiency (PMIDs: 21211618, 24430186). This gene-disease relationship is supported by altered expression and function in patient cells during megakaryopoeisis and proplatelet formation, as well as the rescue of proplatelet formation in patient cells by shRNA knockdown (PMID 24430186). In summary ANKRD26 is definitively associated with autosomal dominant thrombocytopenia 2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

autosomal thrombocytopenia with normal plateletsSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015679

Submitter: Orphanet

thrombocytopenia 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008555

Submitter: Labcorp Genetics (formerly Invitae)

thrombocytopenia 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008555

Submitter: PanelApp Australia

acute myeloid leukemiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0018874

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Thrombocytopenia 2AD

Manifestation: Hematologic

Intervention: Hematologic

Rationale: Individuals may have bleeding tendency, and awareness may allow precautions (eg, in surgical situations) and prompt treatment, which may be beneficial

Comments: A variant in ABCD5 was reported as causative

Refs: 10541317; 10521306; 10891439; 20626622; 21211618

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ANKRD26 variants in ClinVar

7 Conditions Cataloged

Inborn genetic diseasesTotal: 2456

not providedTotal: 1284

not specifiedTotal: 239

Thrombocytopenia 2Total: 191

ANKRD26-related disorderTotal: 132

ThrombocytopeniaTotal: 1

Abnormal bleedingTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_014915.3. 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			9 clinvar	677 clinvar		686
missense			1888 clinvar	171 clinvar	14 clinvar	2073
nonsense	1 clinvar	1 clinvar	26 clinvar	2 clinvar		30
start loss			2 clinvar			2
frameshift		1 clinvar	54 clinvar	1 clinvar		56
splice donor/acceptor (+/-2bp)			23 clinvar			23
Total	1	2	2002	851	14	2870

Highest pathogenic variant AF is 0.000017968072

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_014915.3	RefSeq	NP_055730.2	34	MANE Select
ENST00000376087.5	Ensembl	ENSP00000365255.4	34	MANE Select
NM_001256053.2	RefSeq	NP_001242982.1	34	Standard
ENST00000436985.7	Ensembl	ENSP00000405112.3	34	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

negative regulation of fat cell differentiation

Molecular Function

protein binding

Cellular Component

centrosome

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000376087
Coding exons: 34
Length: 108579
Individuals with no LoFs: 124625
Homozygous LoFs: 0
Heterozygous LoFs: 180
Defined: 124805
p: 0.000721

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.396	855	823	1.04	0.0000387	11402
Missense (PolyPhen)		147	160.19	0.91764		2511
Synonymous	0.161	291	295	0.988	0.0000145	2917
Loss of Function	3.68	53	90.9	0.583	0.00000428	1221

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00078	0.00078	rare
Latino/Admixed American	0.0010	0.0010	notable
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00045	0.00044	rare
Finnish	0.0014	0.0014	notable
European (Non-Finnish)	0.00060	0.00060	rare
South Asian	0.00063	0.00062	rare
Other	0.0010	0.00099	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Acts as a regulator of adipogenesis. Involved in the regulation of the feeding behavior. {ECO:0000250|UniProtKB:Q811D2}.;
Disease: DISEASE: Thrombocytopenia 2 (THC2) [MIM:188000]: Thrombocytopenia is defined by a decrease in the number of platelets in circulating blood, resulting in the potential for increased bleeding and decreased ability for clotting. {ECO:0000269|PubMed:21211618}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.102

Intolerance Scores

LoFtool: 0.985
RVIS EVS: 2.15
RVIS percentile EVS: 97.98

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.287

Gene Damage Prediction

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