CYP21A2
cytochrome P450 family 21 subfamily A member 2, the group of Cytochrome P450 family 21
Basic information
Region (hg38): 6:32038326-32041644
Previous symbols: [ "CYP21", "CYP21B" ]
Links
Phenotypes
GenCC
Source:
- classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Definitive), mode of inheritance: AR
- classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Strong), mode of inheritance: AR
- classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form (Supportive), mode of inheritance: AR
- classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form (Supportive), mode of inheritance: AR
- classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (Definitive), mode of inheritance: AR
Clinical Genomic Database
Source:
| Condition | Inheritance | Intervention Categories | Intervention/Rationale | Manifestation Categories | References |
|---|---|---|---|---|---|
| Adrenal hyperplasia, congenital, due to 21-hydroxylase deficiency | AR | Cardiovascular; Endocrine; Genitourinary; Oncologic | 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 | Cardiovascular; Endocrine; Genitourinary; Oncologic | 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; 22186144 |
ClinVar
This is a list of variants' phenotypes submitted to
- not provided (122 variants)
- Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency (83 variants)
- not specified (48 variants)
- Congenital adrenal hyperplasia (15 variants)
- CYP21A2-related condition (8 variants)
- Inborn genetic diseases (8 variants)
- - (2 variants)
- Carcinoma, adrenocortical, androgen-secreting (1 variants)
- Adenoma, cortisol-producing (1 variants)
- Congenital lipoid adrenal hyperplasia due to STAR deficency (1 variants)
- Vesicoureteral reflux 8;Ehlers-Danlos syndrome due to tenascin-X deficiency (1 variants)
- Hyperandrogenism, nonclassic type, due to 21-hydroxylase deficiency (1 variants)
- Abnormality of the female genitalia (1 variants)
- 21-HYDROXYLASE POLYMORPHISM (1 variants)
- Adrenal hyperplasia (1 variants)
Variants pathogenicity by type
Statistics on ClinVar variants can assist in determining whether a specific variant type in the CYP21A2 gene is commonly pathogenic or not.
In the table, we include only reliable ClinVar variants with their consequences to MANE Select, Mane Plus Clinical transcripts, or transcripts with TSL equals 1. Click the count to view the source variants.
Warning: slight differences between displayed counts and the number of variants in ClinVar may occur, primarily due to (1) the application of a different transcript and/or consequence by our variant effect predictor or (2) differences in clinical significance: we classify Benign/Likely benign variants as Likely benign and Pathogenic/Likely pathogenic variants as Likely pathogenic.
| Variant type | Pathogenic | Likely pathogenic | VUS | Likely benign | Benign | Sum |
|---|---|---|---|---|---|---|
| synonymous | 20 | |||||
| missense | 17 | 26 | 38 | 86 | ||
| nonsense | 11 | |||||
| start loss | 1 | |||||
| frameshift | 14 | |||||
| inframe indel | 2 | |||||
| splice donor/acceptor (+/-2bp) | 4 | |||||
| splice region ? | 4 | 2 | 1 | 7 | ||
| non coding ? | 10 | 11 | 29 | |||
| Total | 38 | 38 | 49 | 19 | 23 |
Highest pathogenic variant AF is 0.00378
Variants in CYP21A2
This is a list of pathogenic ClinVar variants found in the CYP21A2 region.
You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.
| Position | Type | Phenotype | Significance | ClinVar |
|---|---|---|---|---|
| 6-32038342-A-C | CYP21A2-related disorder | Uncertain significance (Jan 22, 2024) | ||
| 6-32038350-C-T | CYP21A2-related disorder | Uncertain significance (Oct 21, 2022) | ||
| 6-32038415-G-A | Likely benign (Jul 26, 2022) | |||
| 6-32038419-C-T | not specified | Benign (Oct 08, 2021) | ||
| 6-32038423-A-G | Pathogenic (Oct 29, 2021) | |||
| 6-32038437-CCTG-C | not specified | Benign (Jul 18, 2017) | ||
| 6-32038437-C-CCTG | 21-HYDROXYLASE POLYMORPHISM • Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | Benign (Jun 01, 1987) | ||
| 6-32038441-C-CT | Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | Likely pathogenic (-) | ||
| 6-32038444-C-A | not specified | Uncertain significance (Feb 14, 2023) | ||
| 6-32038459-C-A | Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | Uncertain significance (Jan 20, 2023) | ||
| 6-32038462-G-T | Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | Uncertain significance (May 11, 2022) | ||
| 6-32038467-C-T | Uncertain significance (Mar 14, 2016) | |||
| 6-32038471-C-T | not specified • Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | Uncertain significance (Apr 25, 2023) | ||
| 6-32038472-G-T | Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | Uncertain significance (May 24, 2019) | ||
| 6-32038482-G-A | Pathogenic (Oct 10, 2022) | |||
| 6-32038490-G-A | Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | Likely pathogenic (Mar 17, 2024) | ||
| 6-32038491-G-T | not specified | Uncertain significance (Apr 19, 2016) | ||
| 6-32038499-G-A | CYP21A2-related disorder | Uncertain significance (Nov 27, 2023) | ||
| 6-32038505-T-TC | Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | Pathogenic (Dec 01, 2001) | ||
| 6-32038511-T-A | Uncertain significance (Jun 20, 2018) | |||
| 6-32038513-C-T | Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | Likely pathogenic (Apr 14, 2023) | ||
| 6-32038514-C-A | Pathogenic (Nov 23, 2018) | |||
| 6-32038514-C-T | Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | Pathogenic (Mar 28, 2023) | ||
| 6-32038516-C-T | Uncertain significance (Aug 23, 2021) | |||
| 6-32038526-C-T | Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency | Uncertain significance (Jan 20, 2023) |
GnomAD
Source:
| Gene | Type | Bio Type | Transcript | Coding Exons | Length |
|---|---|---|---|---|---|
| CYP21A2 | protein_coding | protein_coding | ENST00000418967 | 10 | 3406 |
| pLI Probability LOF Intolerant | pRec Probability LOF Recessive | Individuals with no LOFs | Individuals with Homozygous LOFs | Individuals with Heterozygous LOFs | Defined | p |
|---|---|---|---|---|---|---|
| 0.000260 | 0.985 | 125722 | 0 | 26 | 125748 | 0.000103 |
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible in Transcript | |
|---|---|---|---|---|---|---|
| Missense | 1.15 | 219 | 273 | 0.803 | 0.0000168 | 3086 |
| Missense in Polyphen | 83 | 102.75 | 0.80778 | 1178 | ||
| Synonymous | 1.37 | 99 | 118 | 0.839 | 0.00000754 | 1003 |
| Loss of Function | 2.16 | 9 | 19.2 | 0.469 | 8.44e-7 | 232 |
LoF frequencies by population
| Ethnicity | Sum of pLOFs | p |
|---|---|---|
| African & African-American | 0.0000580 | 0.0000580 |
| Ashkenazi Jewish | 0.00 | 0.00 |
| East Asian | 0.000961 | 0.000816 |
| Finnish | 0.0000924 | 0.0000924 |
| European (Non-Finnish) | 0.0000562 | 0.0000527 |
| Middle Eastern | 0.000961 | 0.000816 |
| South Asian | 0.00 | 0.00 |
| Other | 0.000190 | 0.000163 |
dbNSFP
Source:
- 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.;
- Pathway
- 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;Apparent mineralocorticoid excess syndrome;3-Beta-Hydroxysteroid Dehydrogenase Deficiency;21-hydroxylase deficiency (CYP21);Corticosterone methyl oxidase I deficiency (CMO I);Corticosterone methyl oxidase II deficiency - CMO II;Adrenal Hyperplasia Type 5 or Congenital Adrenal Hyperplasia due to 17 Alpha-hydroxylase Deficiency;Adrenal Hyperplasia Type 3 or Congenital Adrenal Hyperplasia due to 21-hydroxylase Deficiency;Congenital Lipoid Adrenal Hyperplasia (CLAH) or Lipoid CAH;17-alpha-hydroxylase deficiency (CYP17);11-beta-hydroxylase deficiency (CYP11B1);Corticotropin-releasing hormone signaling pathway;Glucocorticoid and Mineralcorticoid Metabolism;Metapathway biotransformation Phase I and II;Phase I - Functionalization of compounds;Metabolism of lipids;Endogenous sterols;Cytochrome P450 - arranged by substrate type;Biological oxidations;Metabolism;Mineralocorticoid biosynthesis;Metabolism of steroid hormones;Metabolism of steroids;C21-steroid hormone biosynthesis and metabolism;Glucocorticoid biosynthesis;glucocorticoid biosynthesis;mineralocorticoid biosynthesis;superpathway of steroid hormone biosynthesis;Steroid hormones
(Consensus)
Recessive Scores
- pRec
- 0.264
Haploinsufficiency Scores
- pHI
- 0.273
- hipred
- Y
- hipred_score
- 0.507
- ghis
- 0.408
Essentials
- essential_gene_CRISPR
- N
- essential_gene_CRISPR2
- S
- essential_gene_gene_trap
- N
- gene_indispensability_pred
- E
- gene_indispensability_score
- 0.810
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | High |
| Cancer | Medium | Medium | Medium |
Mouse Genome Informatics
- Gene name
- Cps1
- Phenotype
- homeostasis/metabolism phenotype; mortality/aging (the observable characteristics related to the ability of a mammalian organism to live and age that are manifested throughout development and life span);
Zebrafish Information Network
- Gene name
- cyp21a2
- Affected structure
- interrenal gland
- Phenotype tag
- abnormal
- Phenotype quality
- hyperplastic
Gene ontology
- Biological process
- steroid biosynthetic process;glucocorticoid biosynthetic process;mineralocorticoid biosynthetic process;steroid metabolic process;sterol metabolic process;oxidation-reduction process
- Cellular component
- endoplasmic reticulum membrane;organelle membrane
- Molecular function
- steroid 21-monooxygenase activity;steroid binding;iron ion binding;steroid hydroxylase activity;heme binding