ANKH

protein-coding

ANKH inorganic pyrophosphate transport regulator, the group of MicroRNA protein coding host genes|Solute carrier family 62

Gene summary

This gene encodes a multipass transmembrane protein that is expressed in joints and other tissues and controls pyrophosphate levels in cultured cells. Progressive ankylosis-mediated control of pyrophosphate levels has been suggested as a possible mechanism regulating tissue calcification and susceptibility to arthritis in higher animals. Mutations in this gene have been associated with autosomal dominant craniometaphyseal dysplasia. [provided by RefSeq, Jul 2008]

Previous symbols:

CCAL2
CMDJ

MANE transcript

NM_054027.6

Inheritance

ClinVar variants

P:9U:142B:105

Top phenotype

Craniometaphyseal dysplasia, autosomal dominant; Chondrocalcinosis 2

gnomAD constraint

pLI —, LoF o/e 0.24

Max pathogenic AF

—

Genomic locus

chr5:14,704,800-14,871,778

External References & Databases

Ensembl (ENSG00000154122)

Transcript & Mutation Effects

hg38 • Region Span ~167.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

chondrocalcinosis 2SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007319

Submitter: Orphanet

chondrocalcinosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007319

Submitter: PanelApp Australia

craniometaphyseal dysplasia, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007397

Submitter: PanelApp Australia

craniometaphyseal dysplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015465

Submitter: Orphanet

craniometaphyseal dysplasia, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007397

Submitter: Labcorp Genetics (formerly Invitae)

craniometaphyseal dysplasia, autosomal dominantSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007397

Submitter: Genomics England PanelApp

chondrocalcinosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007319

Submitter: Labcorp Genetics (formerly Invitae)

chondrocalcinosis 2STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007319

Submitter: Genomics England PanelApp

chondrocalcinosis 2DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007319

Submitter: G2P

craniometaphyseal dysplasia, autosomal dominantDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007397

Submitter: G2P

skeletal dysplasiaMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0018230

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Craniometaphyseal dysplasia, autosomal dominant; Chondrocalcinosis 2AD

Manifestation: Craniofacial; Musculoskeletal

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: 8528213; 9915952; 11326272; 11326338; 12297987; 12297989; 20301634; 20358596; 22150416; 22647861

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ANKH variants in ClinVar

9 Conditions Cataloged

not providedTotal: 303

not specifiedTotal: 62

Craniometaphyseal dysplasia, autosomal dominantTotal: 52

Inborn genetic diseasesTotal: 51

Chondrocalcinosis 2Total: 45

ANKH-related disorderTotal: 17

Intellectual disabilityTotal: 2

Paediatric disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_054027.6. 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			3 clinvar	87 clinvar	4 clinvar	94
missense	3 clinvar	4 clinvar	132 clinvar	14 clinvar		153
nonsense			1 clinvar			1
start loss						0
frameshift	1 clinvar		2 clinvar			3
splice donor/acceptor (+/-2bp)		1 clinvar	4 clinvar			5
Total	4	5	142	101	4	256

Highest pathogenic variant AF is 0.000027364424

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_054027.6	RefSeq	NP_473368.1	12	MANE Select
ENST00000284268.8	Ensembl	ENSP00000284268.6	12	MANE Select
ENST00000505140.1	Ensembl	ENSP00000426332.1	1	Standard
ENST00000646501.1	Ensembl	ENSP00000494403.1	2	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

regulators of bone mineralization
Transport of small molecules
Miscellaneous transport and binding events

Biological Process

skeletal system development
locomotory behavior
regulation of bone mineralization
inorganic diphosphate transport
phosphate ion transmembrane transport

Molecular Function

inorganic phosphate transmembrane transporter activity
phosphate ion transmembrane transporter activity
inorganic diphosphate transmembrane transporter activity

Cellular Component

plasma membrane
integral component of plasma membrane
integral component of membrane
outer membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000284268
Coding exons: 12
Length: 166978
Individuals with no LoFs: 125732
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 125748
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.35	184	298	0.617	0.0000188	3220
Missense (PolyPhen)		38	124.85	0.30435		1349
Synonymous	-1.21	141	124	1.14	0.00000902	995
Loss of Function	3.24	5	21.1	0.237	9.11e-7	263

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.00012	0.00012	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0.000048	0.000046	rare
European (Non-Finnish)	0.000070	0.000070	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulates intra- and extracellular levels of inorganic pyrophosphate (PPi), probably functioning as PPi transporter.;
Disease: DISEASE: Craniometaphyseal dysplasia, autosomal dominant (CMDD) [MIM:123000]: An osteochondrodysplasia characterized by hyperostosis and sclerosis of the craniofacial bones associated with abnormal modeling of the metaphyses. Sclerosis of the skull may lead to asymmetry of the mandible, as well as to cranial nerve compression, that may finally result in hearing loss and facial palsy. {ECO:0000269|PubMed:11326272, ECO:0000269|PubMed:11326338}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.115
RVIS EVS: -0.38
RVIS percentile EVS: 28.01

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.405

Gene Damage Prediction

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