GeneBe

CYP21A2

protein-coding

cytochrome P450 family 21 subfamily A member 2, the group of Cytochrome P450 family 21

Gene summary

This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and hydroxylates steroids at the 21 position. Its activity is required for the synthesis of steroid hormones including cortisol and aldosterone. Mutations in this gene cause congenital adrenal hyperplasia. A related pseudogene is located near this gene; gene conversion events involving the functional gene and the pseudogene are thought to account for many cases of steroid 21-hydroxylase deficiency. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:
  • CYP21
  • CYP21B

MANE transcript

NM_000500.9

Inheritance

AR

ClinVar variants

P:140U:126B:39

Top phenotype

Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr6:32,038,327-32,041,644

External References & Databases

Ensembl (ENSG00000231852)NCBI Gene (1589)OMIM (613815)HGNC:2600GenCCUniProt (P08686)AlphaFoldClinVar (CYP21A2)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~3.3 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

classic congenital adrenal hyperplasia due to 21-hydroxylase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008728

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing formSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017840

Submitter: Orphanet

classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting formSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0017839

Submitter: Orphanet

classic congenital adrenal hyperplasia due to 21-hydroxylase deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008728

Submitter: Myriad Women's Health

classic congenital adrenal hyperplasia due to 21-hydroxylase deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008728

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiencyAR

Manifestation: Cardiovascular; Endocrine; Genitourinary; Oncologic

Intervention: Cardiovascular; Endocrine; Genitourinary; Oncologic

Rationale: In classic 21-OHD CAH, medical therapy (with glucocorticoid replacement), including with stress dosing glucocorticoid replacement therapy is beneficial; In the salt-wasting form, medical therapy (eg, with mineralocorticoid therapy, sodium chloride) can be beneficial; Surveillance and early treatment for neoplasms such as testicular adrenal rest tumors is indicated, as is surveillance related to multiple factors such as BMI, bone mineral density, fertility, and cardiovascular risk factors

Refs: 13968788; 4298539; 835605; 152409; 6449518; 6102330; 317470; 6095106; 2989686; 3030300; 3491959; 3038528; 2667968; 2783976; 2247119; 1311000; 1644925; 7957400; 8855797; 8626833; 8923864; 9360525; 9329356; 9100612; 8989258; 9851787; 9661649; 9613359; 9829208; 10372672; 10084573; 10199755; 10720040; 11070100; 0720048; 11397874; 11232002; 11397897; 11739428; 12107196; 12213842; 12183722; 12788866; 12930931; 12915679; 12843131; 14764770; 16926248; 17299071; 17878254; 17535996; 17148562; 17456574; 8989258; 18381579; 20392211; 20301350; 22841790; 23073904; 22157069; 22241917; 22802425; 23044877; 22186144Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYP21A2 variants in ClinVar

14 Conditions Cataloged
21-Hydroxylase-Deficient Congenital Adrenal HyperplasiaTotal: 198
not providedTotal: 146
CYP21A2-related disorderTotal: 85
not specifiedTotal: 64
Inborn genetic diseasesTotal: 27
Congenital adrenal hyperplasiaTotal: 22
Fetal anomalies with a likely genetic causeTotal: 2
Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiencyTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000500.9. 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
2
clinvar
5
clinvar
24
clinvar
5
clinvar
 36
missense
24
clinvar
59
clinvar
118
clinvar
10
clinvar
 211
nonsense
13
clinvar
5
clinvar
 18
start loss
1
clinvar
 1
frameshift
12
clinvar
15
clinvar
3
clinvar
 30
splice donor/acceptor (+/-2bp)
5
clinvar
4
clinvar
 9
Total5585126345305

Highest pathogenic variant AF is 0.007159243

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000500.9RefSeqNP_000491.410MANE Select
ENST00000644719.2EnsemblENSP00000496625.110MANE Select
NM_001128590.4RefSeqNP_001122062.39Standard
NM_001368143.2RefSeqNP_001355072.18Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
cyp21a2Danio rerio

Structure: interrenal gland

Quality: hyperplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Cortisol synthesis and secretion - Homo sapiens (human)
  • Aldosterone synthesis and secretion - Homo sapiens (human)
  • Cushing,s syndrome - Homo sapiens (human)
  • Steroid hormone biosynthesis - Homo sapiens (human)
  • Steroidogenesis

Biological Process

  • steroid biosynthetic process
  • glucocorticoid biosynthetic process
  • mineralocorticoid biosynthetic process
  • steroid metabolic process
  • sterol metabolic process

Molecular Function

  • steroid 21-monooxygenase activity
  • steroid binding
  • iron ion binding
  • steroid hydroxylase activity
  • heme binding

Cellular Component

  • endoplasmic reticulum membrane
  • organelle membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000418967
Coding exons
10
Length
3406
Individuals with no LoFs
125722
Homozygous LoFs
0
Heterozygous LoFs
26
Defined
125748
p
0.000103
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.152192730.8030.00001683086
Missense (PolyPhen)83102.750.807781178
Synonymous1.37991180.8390.000007541003
Loss of Function2.16919.20.4698.44e-7232

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian0.000960.00082rare
Finnish0.0000920.000092rare
European (Non-Finnish)0.0000560.000053rare
South Asian00.0absent
Other0.000190.00016rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Specifically catalyzes the 21-hydroxylation of steroids. Required for the adrenal synthesis of mineralocorticoids and glucocorticoids (PubMed:22014889). {ECO:0000269|PubMed:22014889, ECO:0000269|PubMed:25855791, ECO:0000269|PubMed:27721825}.;
Disease
DISEASE: Adrenal hyperplasia 3 (AH3) [MIM:201910]: A form of congenital adrenal hyperplasia, a common recessive disease due to defective synthesis of cortisol. Congenital adrenal hyperplasia is characterized by androgen excess leading to ambiguous genitalia in affected females, rapid somatic growth during childhood in both sexes with premature closure of the epiphyses and short adult stature. Four clinical types: 'salt wasting' (SW, the most severe type), 'simple virilizing' (SV, less severely affected patients), with normal aldosterone biosynthesis, 'non-classic form' or late- onset (NC or LOAH) and 'cryptic' (asymptomatic). {ECO:0000269|PubMed:10051010, ECO:0000269|PubMed:10094562, ECO:0000269|PubMed:10198222, ECO:0000269|PubMed:10364682, ECO:0000269|PubMed:10391209, ECO:0000269|PubMed:10408778, ECO:0000269|PubMed:10408786, ECO:0000269|PubMed:10443693, ECO:0000269|PubMed:10496074, ECO:0000269|PubMed:10720040, ECO:0000269|PubMed:11232002, ECO:0000269|PubMed:11598371, ECO:0000269|PubMed:11600539, ECO:0000269|PubMed:11746135, ECO:0000269|PubMed:12213891, ECO:0000269|PubMed:12222711, ECO:0000269|PubMed:12788866, ECO:0000269|PubMed:12887291, ECO:0000269|PubMed:12915679, ECO:0000269|PubMed:1406699, ECO:0000269|PubMed:1406709, ECO:0000269|PubMed:14676460, ECO:0000269|PubMed:14715874, ECO:0000269|PubMed:1496017, ECO:0000269|PubMed:15110320, ECO:0000269|PubMed:15126570, ECO:0000269|PubMed:16046588, ECO:0000269|PubMed:1644925, ECO:0000269|PubMed:16984992, ECO:0000269|PubMed:18319307, ECO:0000269|PubMed:18381579, ECO:0000269|PubMed:18445671, ECO:0000269|PubMed:1864962, ECO:0000269|PubMed:1937474, ECO:0000269|PubMed:20080860, ECO:0000269|PubMed:2072928, ECO:0000269|PubMed:21169732, ECO:0000269|PubMed:22014889, ECO:0000269|PubMed:2303461, ECO:0000269|PubMed:27721825, ECO:0000269|PubMed:3038528, ECO:0000269|PubMed:3257825, ECO:0000269|PubMed:3260007, ECO:0000269|PubMed:3267225, ECO:0000269|PubMed:3497399, ECO:0000269|PubMed:3871526, ECO:0000269|PubMed:7749410, ECO:0000269|PubMed:8478006, ECO:0000269|PubMed:8485582, ECO:0000269|PubMed:8989258, ECO:0000269|PubMed:9067760, ECO:0000269|PubMed:9187661, ECO:0000269|PubMed:9497336, ECO:0000269|PubMed:9580109}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.264

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
S
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.810

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumHigh
CancerMediumMediumMedium
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