AK2

protein-coding

adenylate kinase 2, the group of Adenylate kinases

Gene summary

Adenylate kinases are involved in regulating the adenine nucleotide composition within a cell by catalyzing the reversible transfer of phosphate groups among adenine nucleotides. Three isozymes of adenylate kinase, namely 1, 2, and 3, have been identified in vertebrates; this gene encodes isozyme 2. Expression of these isozymes is tissue-specific and developmentally regulated. Isozyme 2 is localized in the mitochondrial intermembrane space and may play a role in apoptosis. Mutations in this gene are the cause of reticular dysgenesis. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 1 and 2.[provided by RefSeq, Nov 2010]

MANE transcript

NM_001625.4

Inheritance

ClinVar variants

P:31U:107B:63

Top phenotype

Reticular dysgenesis

gnomAD constraint

pLI —, LoF o/e 0.68

Max pathogenic AF

—

Genomic locus

chr1:33,007,986-33,080,996

External References & Databases

Ensembl (ENSG00000004455)

Transcript & Mutation Effects

hg38 • Region Span ~73.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

reticular dysgenesisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009973

Submitter: Ambry Genetics

reticular dysgenesisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009973

Submitter: Orphanet

reticular dysgenesisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009973

Submitter: Labcorp Genetics (formerly Invitae)

reticular dysgenesisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009973

Submitter: PanelApp Australia

reticular dysgenesisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009973

Submitter: G2P

reticular dysgenesisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009973

Submitter: ClinGen

AK2 was first reported in relation to autosomal recessive reticular dysgenesis in 2009 (Pannicke U, et al., 2009, PMID: 19043417; Lagresle-Peyrou C, et al., 2009, PMID: 19043416). AK2 encodes adenylate kinase 2, a mitochondrial protein involved in regulating the adenine nucleotide composition within a cell by catalyzing the reversible transfer of the terminal phosphate group between ATP and AMP. It plays an important role in cellular energy homeostasis and in adenine nucleotide metabolism, particularly within the myeloid and lymphoid lineages, as well as in the stria vascularis of the inner ear, where AK1 isozyme expression is absent or low (PMIDs: 19043417, 19043416). Impairment of AK2 activity in humans leads to the severe lymphocyte and granulocyte differentiation defects and sensorineural deafness characteristic for reticular dysgenesis. Biallelic loss of function variants as associated with a SCID presentation, while hypomorphic alleles may lead to less severe presentations (PMID: 31862378). Curated evidence supporting the gene-disease relationship includes 9 probands with AK2 variants who have been reported in 2 publications (PMIDs: 19043417, 19043416). Clinically unaffected parents were confirmed heterozygous for AK2 variants, immunological phenotypes of carriers were not assessed. This gene-disease relationship is also supported by experimental evidence, including its biochemical function in energy metabolism (PMID: 6182143), which is altered by shRNA knockdown in non-patient cells (PMID: 26270350), and in patient cells (PMID: 19043417), but can be rescued by wild type in patient cells (PMID: 19043416). Models have been used to recapitulate the profound impairment of lymphoid and myeloid development in iPS cells or zebrafish (PMID: 26150473). More evidence is available in the literature, but the maximum score for genetic evidence has been reached. In summary, AK2 is definitively associated with autosomal recessive reticular dysgenesis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen SCID/CID Working Group on 05/20/2021.

Clinical Genomic Database (CGD)

Reticular dysgenesisAR

Manifestation: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic

Intervention: Allergy/Immunology/Infectious; Audiologic/Otolaryngologic

Rationale: Individuals typically die in early infancy due to severe infections; Early diagnosis allowing HSCT can be effective

Refs: 13840590; 6132037; 19043416; 19043417

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AK2 variants in ClinVar

6 Conditions Cataloged

Reticular dysgenesisTotal: 188

not providedTotal: 46

not specifiedTotal: 35

Inborn genetic diseasesTotal: 32

AK2-related disorderTotal: 21

Severe combined immunodeficiency diseaseTotal: 9

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001625.4. 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			1 clinvar	51 clinvar	1 clinvar	53
missense	1 clinvar	5 clinvar	93 clinvar	11 clinvar		110
nonsense	4 clinvar	2 clinvar				6
start loss	2 clinvar					2
frameshift	5 clinvar	7 clinvar	7 clinvar			19
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	6 clinvar			11
Total	13	18	107	62	1	201

Highest pathogenic variant AF is 0.000043991124

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001625.4	RefSeq	NP_001616.1	6	MANE Select
ENST00000672715.1	Ensembl	ENSP00000499935.1	6	MANE Select
NM_001199199.3	RefSeq	NP_001186128.1	7	Standard
NM_001319139.3	RefSeq	NP_001306068.1	6	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ak2	Danio rerio	Structure: granulocyte Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

ak2

Danio rerio

Structure: granulocyte

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Purine metabolism - Homo sapiens (human)
Thiamine metabolism - Homo sapiens (human)
Tenofovir/Adefovir Pathway, Pharmacodynamics
Tenofovir/Adefovir Pathway, Pharmacokinetics
Adefovir Dipivoxil Metabolism Pathway

Biological Process

ADP biosynthetic process
nucleobase-containing small molecule interconversion
phosphorylation
AMP metabolic process
ATP metabolic process

Molecular Function

adenylate kinase activity
ATP binding

Cellular Component

mitochondrial intermembrane space
extracellular exosome
sperm mitochondrial sheath

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000354858
Coding exons: 6
Length: 73013
Individuals with no LoFs: 125721
Homozygous LoFs: 0
Heterozygous LoFs: 27
Defined: 125748
p: 0.000107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.0718	133	135	0.983	0.00000755	1548
Missense (PolyPhen)		38	46.117	0.82399		599
Synonymous	-2.17	69	49.6	1.39	0.00000264	468
Loss of Function	1.02	8	11.8	0.678	7.53e-7	129

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00012	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0.000099	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0.00014	0.00014	rare
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000069	0.000065	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Catalyzes the reversible transfer of the terminal phosphate group between ATP and AMP. Plays an important role in cellular energy homeostasis and in adenine nucleotide metabolism. Adenylate kinase activity is critical for regulation of the phosphate utilization and the AMP de novo biosynthesis pathways. Plays a key role in hematopoiesis. {ECO:0000255|HAMAP- Rule:MF_03168, ECO:0000269|PubMed:19043416}.;
Disease: DISEASE: Reticular dysgenesis (RDYS) [MIM:267500]: A fatal form of severe combined immunodeficiency, characterized by absence of granulocytes, almost complete deficiency of lymphocytes in peripheral blood, hypoplasia of the thymus and secondary lymphoid organs, and lack of innate and adaptive humoral and cellular immunity, leading to fatal septicemia within days after birth. In bone marrow of individuals with reticular dysgenesis, myeloid differentiation is blocked at the promyelocytic stage, whereas erythro- and megakaryocytic maturation is generally normal. Inheritance is autosomal recessive. {ECO:0000269|PubMed:19043416, ECO:0000269|PubMed:19043417}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.358

Intolerance Scores

LoFtool: 0.555
RVIS EVS: 0.22
RVIS percentile EVS: 68.13

Essentials

Essential (CRISPR): E
Essential (CRISPR2): N
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.991

Gene Damage Prediction

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