GeneBe

AKR1C2

protein-coding

aldo-keto reductase family 1 member C2, the group of Aldo-keto reductases

Gene summary

This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols using NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme binds bile acid with high affinity, and shows minimal 3-alpha-hydroxysteroid dehydrogenase activity. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

Previous symbols:
  • DDH2
  • TDD

MANE transcript

NM_001393392.1

Inheritance

AR

ClinVar variants

P:5U:48B:13

Top phenotype

46,XY sex reversal 8

gnomAD constraint

pLI —, LoF o/e 0.96

Max pathogenic AF

—

Genomic locus

chr10:4,987,775-5,018,031

External References & Databases

Ensembl (ENSG00000151632)NCBI Gene (1646)OMIM (600450)HGNC:385GenCCUniProt (P52895)AlphaFoldClinVar (AKR1C2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~30.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

46,XY disorder of sex development due to testicular 17,20-desmolase deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013664

Submitter: PanelApp Australia

46,XY disorder of sex development due to testicular 17,20-desmolase deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013664

Submitter: Orphanet

46,XY disorder of sex development due to testicular 17,20-desmolase deficiencyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013664

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

46,XY sex reversal 8AR

Manifestation: Endocrine; Genitourinary; Oncologic

Intervention: Genitourinary; Oncologic

Rationale: Surveillance and/or awareness of cancer risk, and preventive measures may be beneficial to reduce the risk of gonadal tumors

Refs: 4352099; 21802064Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to AKR1C2 variants in ClinVar

6 Conditions Cataloged
not specifiedTotal: 52
46,XY disorder of sex development due to testicular 17,20-desmolase deficiencyTotal: 10
AKR1C2-related disorderTotal: 9
not providedTotal: 6
CIC-rearranged sarcomaTotal: 1
See casesTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001393392.1. 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.

EffectPLPVUSLBBSum
synonymous
10
clinvar
 10
missense
4
clinvar
44
clinvar
2
clinvar
1
clinvar
 51
nonsense
1
clinvar
 1
start loss
0
frameshift
3
clinvar
 3
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total414812166

Highest pathogenic variant AF is 0.000011773395

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 29 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001393392.1RefSeqNP_001380321.19MANE Select
ENST00000380753.9EnsemblENSP00000370129.49MANE Select
NM_001135241.3RefSeqNP_001128713.14Standard
NM_001321027.2RefSeqNP_001307956.18Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Steroid hormone biosynthesis - Homo sapiens (human)
  • Chemical carcinogenesis - Homo sapiens (human)
  • Benzo(a)pyrene metabolism
  • Metapathway biotransformation Phase I and II
  • Prostaglandin Synthesis and Regulation

Biological Process

  • prostaglandin metabolic process
  • G protein-coupled receptor signaling pathway
  • digestion
  • steroid metabolic process
  • positive regulation of cell population proliferation

Molecular Function

  • alditol:NADP+ 1-oxidoreductase activity
  • alcohol dehydrogenase (NADP+) activity
  • steroid dehydrogenase activity
  • oxidoreductase activity
  • oxidoreductase activity, acting on NAD(P)H, quinone or similar compound as acceptor

Cellular Component

  • cytoplasm
  • cytosol

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000380753
Coding exons
9
Length
30257
Individuals with no LoFs
125516
Homozygous LoFs
0
Heterozygous LoFs
231
Defined
125747
p
0.000919
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.8731761461.200.000007132083
Missense (PolyPhen)7363.3431.1524904
Synonymous-1.877758.81.310.00000306610
Loss of Function0.1401616.60.9630.00000101212

Population LoF Frequency

PopulationCAFp-valueStatus
African0.000550.00055rare
Latino/Admixed American0.000520.00052rare
Ashkenazi Jewish0.00610.0061notable
East Asian0.00250.0024notable
Finnish0.0000460.000046rare
European (Non-Finnish)0.000320.00032rare
South Asian0.00180.0018notable
Other0.000980.00098rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Works in concert with the 5-alpha/5-beta-steroid reductases to convert steroid hormones into the 3-alpha/5-alpha and 3-alpha/5-beta-tetrahydrosteroids. Catalyzes the inactivation of the most potent androgen 5-alpha-dihydrotestosterone (5-alpha- DHT) to 5-alpha-androstane-3-alpha,17-beta-diol (3-alpha-diol). Has a high bile-binding ability. {ECO:0000269|PubMed:15929998, ECO:0000269|PubMed:17034817, ECO:0000269|PubMed:17442338, ECO:0000269|PubMed:8573067}.;

Intolerance Scores

LoFtool
0.916
RVIS EVS
-0.09
RVIS percentile EVS
46.74

Essentials

Essential (CRISPR)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.908

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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