CYP11B2

protein-coding

cytochrome P450 family 11 subfamily B member 2, the group of Cytochrome P450 family 11

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 mitochondrial inner membrane. The enzyme has steroid 18-hydroxylase activity to synthesize aldosterone and 18-oxocortisol as well as steroid 11 beta-hydroxylase activity. Mutations in this gene cause corticosterone methyl oxidase deficiency. [provided by RefSeq, Jul 2008]

Previous symbols:

CYP11B

MANE transcript

NM_000498.3

Inheritance

AR, AD

ClinVar variants

P:134U:174B:303

Top phenotype

Corticosterone methyloxidase type I deficiency; Corticosterone methyloxidase type II deficiency; Glucocorticoid-remediable aldosteronism

gnomAD constraint

pLI —, LoF o/e 1.13

Max pathogenic AF

—

Genomic locus

chr8:142,910,559-142,917,843

External References & Databases

Ensembl (ENSG00000179142)

Transcript & Mutation Effects

hg38 • Region Span ~7.3 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

corticosterone methyloxidase type 1 deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008751

Submitter: Natera

corticosterone methyloxidase type 1 deficiencyMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0008751

Submitter: Ambry Genetics

familial hyperreninemic hypoaldosteronism type 2DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011754

Submitter: ClinGen

The *CYP11B2* gene is located on chromosome 8 at q24.3 and encodes the cytochrome P450 family 11 subfamily B member 2. Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their inheritance pattern or phenotypic spectrum. Therefore, the following disease entities have been lumped into one disease entity: congenital hypoaldosteronism due to CMO I deficiency (OMIM:203400) and congenital hypoaldosteronism due to CMO II deficiency (OMIM:610600). The preferred disease name suggested for this grouping of disorders is ‘familial hyperreninemic hypoaldosteronism - *CYP11B2*’. *CYP11B2* was first reported in relation to autosomal recessive familial hyperreninemic hypoaldosteronism in 1992 (Pascoe et al., PMID: 1594605). The mechanism of pathogenicity is known to be loss of function. Familial hyperreninemic hypoaldosteronism typically presents in infancy as a life-threatening electrolyte imbalance, characterized by failure to thrive, recurrent vomiting, and severe dehydration. A history of diarrhea, lethargy, poor weight gain, and poor feeding since birth may also be present. At least 9 variants (missense, in-frame indel, nonsense, frameshift, canonical splice site) have been reported in 5 probands in 5 publications (PMIDs: 12788848, 23018980, 31302112, 32539318, 34243750 included in this curation). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached, considering case-level data. This gene-disease relationship is also supported by expression studies and biochemical function. CYP11B2 is expressed in the zona glomerulosa of the adrenal glands and is used to synthesize aldosterone, with biallelic variation leading to aldosterone deficiency causing disease (PMIDs: 20200334, 21237269). A total of 1/6 pts. for experimental evidence was reached. In summary, there is definitive evidence supporting the relationship between *CYP11B2* and autosomal recessive familial hyperreninemic hypoaldosteronism. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

corticosterone methyloxidase type 2 deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0012524

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Corticosterone methyloxidase type I deficiency; Corticosterone methyloxidase type II deficiency; Glucocorticoid-remediable aldosteronismAD/AR

Manifestation: Endocrine; Genitourinary; Oncologic

Intervention: Endocrine; Genitourinary; Oncologic

Rationale: In Corticosterone methyloxidase deficiency, treatment of salt wasting (eg, with salt/mineralocorticoid supplementation) has shown success; In Glucocorticoid-remediable aldosteronism, medical treatment (eg, with glucocorticoids) can be beneficial; Surgical interventions may decrease the risk of gonadal tumors

Comments: Glucocorticoid-remediable aldosteronism involves a fusion gene (with CYP11B1)

Refs: 14212087; 14250395; 295679; 4121586; 838841; 6268979; 2044581; 1731223; 1472060; 1601005; 1594605; 8439335; 7550315; 8825044; 9360501; 9814506; 10566645; 10999827; 10852446; 11238478; 12107222; 18178501; 19116236; 20494601; 22465514

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CYP11B2 variants in ClinVar

15 Conditions Cataloged

not providedTotal: 542

Corticosterone 18-monooxygenase deficiencyTotal: 199

Corticosterone methyloxidase type 2 deficiencyTotal: 193

Corticosterone methyl oxidase type II deficiencyTotal: 160

Inborn genetic diseasesTotal: 66

Glucocorticoid-remediable aldosteronismTotal: 51

not specifiedTotal: 48

CYP11B2-related disorderTotal: 22

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000498.3. 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	1 clinvar	6 clinvar	262 clinvar	4 clinvar	274
missense	4 clinvar	19 clinvar	165 clinvar	35 clinvar	2 clinvar	225
nonsense	16 clinvar	15 clinvar				31
start loss		1 clinvar				1
frameshift	25 clinvar	18 clinvar	1 clinvar			44
splice donor/acceptor (+/-2bp)	7 clinvar	27 clinvar	2 clinvar			36
Total	53	81	174	297	6	611

Highest pathogenic variant AF is 0.00012177529

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Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_000498.3	RefSeq	NP_000489.3	9	MANE Select
ENST00000323110.2	Ensembl	ENSP00000325822.2	9	MANE Select
ENST00000945895.1	Ensembl	ENSP00000615954.1	9	Standard
ENST00000945895.2	Ensembl	ENSP00000615954.1	9	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Agents Acting on the Renin-Angiotensin System Pathway, Pharmacodynamics
Aldosterone synthesis and secretion - Homo sapiens (human)
Steroid hormone biosynthesis - Homo sapiens (human)
ACE Inhibitor Pathway, Pharmacodynamics
Steroidogenesis

Biological Process

regulation of blood volume by renal aldosterone
renal water homeostasis
C21-steroid hormone biosynthetic process
glucocorticoid biosynthetic process
mineralocorticoid biosynthetic process

Molecular Function

steroid 11-beta-monooxygenase activity
iron ion binding
steroid hydroxylase activity
heme binding
corticosterone 18-monooxygenase activity

Cellular Component

mitochondrion
mitochondrial inner membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000323110
Coding exons: 9
Length: 7285
Individuals with no LoFs: 125690
Homozygous LoFs: 0
Heterozygous LoFs: 58
Defined: 125748
p: 0.000231

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.849	330	289	1.14	0.0000197	3258
Missense (PolyPhen)		109	106.8	1.0206		1270
Synonymous	-1.18	138	121	1.14	0.00000807	1016
Loss of Function	-0.598	26	22.9	1.13	0.00000128	236

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00052	0.00049	rare
Latino/Admixed American	0.00014	0.00014	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00044	0.00044	rare
Finnish	0.000046	0.000046	rare
European (Non-Finnish)	0.00026	0.00025	rare
South Asian	0.00020	0.00020	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Preferentially catalyzes the conversion of 11- deoxycorticosterone to aldosterone via corticosterone and 18- hydroxycorticosterone. {ECO:0000269|PubMed:23322723}.;
Disease: DISEASE: Corticosterone methyloxidase 1 deficiency (CMO-1 deficiency) [MIM:203400]: Autosomal recessive disorder of aldosterone biosynthesis. There are two biochemically different forms of selective aldosterone deficiency be termed corticosterone methyloxidase (CMO) deficiency type 1 and type 2. In CMO-1 deficiency, aldosterone is undetectable in plasma, while its immediate precursor, 18-hydroxycorticosterone, is low or normal. {ECO:0000269|PubMed:11238478, ECO:0000269|PubMed:9177280}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Corticosterone methyloxidase 2 deficiency (CMO-2 deficiency) [MIM:610600]: Autosomal recessive disorder of aldosterone biosynthesis. In CMO-2 deficiency, aldosterone can be low or normal, but at the expense of increased secretion of 18- hydroxycorticosterone. Consequently, patients have a greatly increased ratio of 18-hydroxycorticosterone to aldosterone and a low ratio of corticosterone to 18-hydroxycorticosterone in serum. {ECO:0000269|PubMed:12788848, ECO:0000269|PubMed:1346492, ECO:0000269|PubMed:1594605, ECO:0000269|PubMed:9625333, ECO:0000269|PubMed:9814506}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Hyperaldosteronism, familial, 1 (HALD1) [MIM:103900]: A disorder characterized by hypertension, variable hyperaldosteronism, and abnormal adrenal steroid production, including 18-oxocortisol and 18-hydroxycortisol. There is significant phenotypic heterogeneity, and some individuals never develop hypertension. Note=The disease is caused by mutations affecting the gene represented in this entry. The molecular defect causing hyperaldosteronism familial 1 is an anti-Lepore-type fusion of the CYP11B1 and CYP11B2 genes. The hybrid gene has the promoting part of CYP11B1, ACTH-sensitive, and the coding part of CYP11B2.;

Recessive Scores

pRec: 0.172

Intolerance Scores

LoFtool: 0.917
RVIS EVS: 0.56
RVIS percentile EVS: 81.67

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.878

Gene Damage Prediction

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