NR3C2

nuclear receptor subfamily 3 group C member 2, the group of Nuclear receptor subfamily 3 group C

Basic information

Region (hg38): 4:148078761-148444698

Previous symbols: [ "MLR" ]

Links

ENSG00000151623 ∙ ∙ OMIM:600983 ∙ HGNC:7979 ∙ Uniprot:P08235 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• autosomal dominant pseudohypoaldosteronism type 1 (Definitive), mode of inheritance: AD
• autosomal dominant pseudohypoaldosteronism type 1 (Definitive), mode of inheritance: AD
• autosomal dominant pseudohypoaldosteronism type 1 (Supportive), mode of inheritance: AD
• pseudohyperaldosteronism type 2 (Limited), mode of inheritance: Unknown
• autosomal dominant pseudohypoaldosteronism type 1 (Strong), mode of inheritance: AD
• pseudohyperaldosteronism type 2 (Limited), mode of inheritance: AD
• autosomal dominant pseudohypoaldosteronism type 1 (Definitive), mode of inheritance: AD

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Pseudohypoaldosteronism type I, autosomal dominant; Hypertension, early-onset, autosomal dominant, with exacerbation in pregnancy	AD	Obstetric; Pharmacogenomic; Renal	In Pseudohypoaldosteronism type I, autosomal dominant Although the disorder may eventually become asymptomatic, individuals can present with neonatal salt wasting, and prompt recognition and treatment of electrolyte imbalances (eg, with sodium supplementation) can be beneficial; In Hypertension, early-onset, autosomal dominant, with exacerbation in pregnancy, hypertension can be severe, and present relatively early in life, and additionally may be exacerbated in pregnancy, and may be accompanied by findings such as hypokalemia, and may necessitate interventions including delivery; It has been suggested the spironolactone is contraindicated	Obstetric; Renal	1939532; 9662404; 10884226; 11134129; 11344206; 12788847; 16954160; 16972228; 20453518; 21159846; 21903996; 21932599

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the NR3C2 gene.

• Autosomal dominant pseudohypoaldosteronism type 1 (142 variants)
• not provided (88 variants)
• Inborn genetic diseases (16 variants)
• Pseudohyperaldosteronism type 2;Autosomal dominant pseudohypoaldosteronism type 1 (10 variants)
• not specified (8 variants)
• NR3C2-related condition (4 variants)
• Autosomal dominant pseudohypoaldosteronism type 1;Pseudohyperaldosteronism type 2 (2 variants)
• Pseudohypoaldosteronism (1 variants)
• See cases (1 variants)
• Autism spectrum disorder (1 variants)
• Pseudohyperaldosteronism type 2 (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the NR3C2 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			5	17	10	32
missense	1	3	53	13	5	75
nonsense	6	5	1			12
start loss						0
frameshift	2	3				5
inframe indel			1			1
splice donor/acceptor (+/-2bp)		1				1
splice region			3	3	2	8
non coding			47	10	34	91
Total	9	12	107	40	49

Variants in NR3C2

This is a list of pathogenic ClinVar variants found in the NR3C2 region.

You can filter this list by clicking the number of variants in the Variants pathogenicity by type table.

Position	Type	Phenotype	Significance	ClinVar
4-148078763-G-A		Autosomal dominant pseudohypoaldosteronism type 1	Likely benign (Jun 14, 2016)
4-148078766-A-C		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jan 19, 2018)
4-148078873-C-T		Autosomal dominant pseudohypoaldosteronism type 1	Benign (Jan 13, 2018)
4-148078934-A-G		Autosomal dominant pseudohypoaldosteronism type 1	Benign (Jan 13, 2018)
4-148078956-A-G		Autosomal dominant pseudohypoaldosteronism type 1	Benign (Jan 12, 2018)
4-148078960-A-G		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jan 15, 2018)
4-148078976-G-T		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jan 13, 2018)
4-148078990-A-G		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jan 12, 2018)
4-148078999-A-G		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jan 12, 2018)
4-148079048-A-G		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jan 13, 2018)
4-148079055-A-C		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jan 12, 2018)
4-148079256-C-T		Autosomal dominant pseudohypoaldosteronism type 1	Benign (Jan 13, 2018)
4-148079279-T-G		Autosomal dominant pseudohypoaldosteronism type 1	Benign (Jan 13, 2018)
4-148079436-C-CTAA		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jun 14, 2016)
4-148079500-ATAAT-A		Autosomal dominant pseudohypoaldosteronism type 1	Likely benign (Jun 14, 2016)
4-148079542-C-T		Autosomal dominant pseudohypoaldosteronism type 1	Benign (Jan 12, 2018)
4-148079547-T-C		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jan 12, 2018)
4-148079570-T-C		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jan 13, 2018)
4-148079586-T-C		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jan 12, 2018)
4-148079614-A-AAGAT		Autosomal dominant pseudohypoaldosteronism type 1	Likely benign (Jun 14, 2016)
4-148079669-CCAAA-C		Autosomal dominant pseudohypoaldosteronism type 1	Likely benign (Jun 14, 2016)
4-148079799-C-CTCTA		Autosomal dominant pseudohypoaldosteronism type 1	Likely benign (Jun 14, 2016)
4-148079836-T-C		Autosomal dominant pseudohypoaldosteronism type 1	Benign (Jan 13, 2018)
4-148079850-CG-C		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jun 14, 2016)
4-148079851-G-A		Autosomal dominant pseudohypoaldosteronism type 1	Uncertain significance (Jan 12, 2018)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
NR3C2	protein_coding	protein_coding	ENST00000358102	8	365938

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.837	0.163	125736	0	12	125748	0.0000477

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	2.10	390	525	0.743	0.0000288	6424
Missense in Polyphen		33	65.203	0.50611		712
Synonymous	-0.381	219	212	1.03	0.0000133	1961
Loss of Function	4.79	8	41.2	0.194	0.00000267	471

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000148	0.000148
Ashkenazi Jewish	0.0000993	0.0000992
East Asian	0.00	0.00
Finnish	0.0000462	0.0000462
European (Non-Finnish)	0.0000441	0.0000439
Middle Eastern	0.00	0.00
South Asian	0.0000327	0.0000327
Other	0.00	0.00

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Receptor for both mineralocorticoids (MC) such as aldosterone and glucocorticoids (GC) such as corticosterone or cortisol. Binds to mineralocorticoid response elements (MRE) and transactivates target genes. The effect of MC is to increase ion and water transport and thus raise extracellular fluid volume and blood pressure and lower potassium levels. {ECO:0000269|PubMed:3037703}.
• Disease: DISEASE: Pseudohypoaldosteronism 1, autosomal dominant (PHA1A) [MIM:177735]: A salt wasting disease resulting from target organ unresponsiveness to mineralocorticoids. PHA1A is a mild form characterized by target organ defects confined to kidney. Patients may present with neonatal renal salt wasting with hyperkalaemic acidosis despite high aldosterone levels. These patients improve with age and usually become asymptomatic without treatment. {ECO:0000269|PubMed:11134129, ECO:0000269|PubMed:12788847, ECO:0000269|PubMed:16954160, ECO:0000269|PubMed:16972228}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Early-onset hypertension with severe exacerbation in pregnancy (EOHSEP) [MIM:605115]: Inheritance is autosomal dominant. The disease is characterized by the onset of severe hypertension before the age of 20, and by suppression of aldosterone secretion. {ECO:0000269|PubMed:10884226, ECO:0000269|PubMed:15908963, ECO:0000269|PubMed:15967794}. Note=The disease is caused by mutations affecting the gene represented in this entry.
• Pathway: Agents Acting on the Renin-Angiotensin System Pathway, Pharmacodynamics;Aldosterone-regulated sodium reabsorption - Homo sapiens (human);ACE Inhibitor Pathway, Pharmacodynamics;Polythiazide Action Pathway;Methyclothiazide Action Pathway;Bumetanide Action Pathway;Spironolactone Action Pathway;Eplerenone Action Pathway;Triamterene Action Pathway;Amiloride Action Pathway;Ethacrynic Acid Action Pathway;Quinethazone Action Pathway;Bendroflumethiazide Action Pathway;Chlorthalidone Action Pathway;Trichlormethiazide Action Pathway;Iminoglycinuria;Lysinuric Protein Intolerance;Blue diaper syndrome;Lysinuric protein intolerance (LPI);Cystinuria;Indapamide Action Pathway;Furosemide Action Pathway;Torsemide Action Pathway;Hartnup Disorder;Glucose Transporter Defect (SGLT2);Kidney Function;Glucose Transporter Defect (SGLT2);Metolazone Action Pathway;Hydrochlorothiazide Action Pathway;Cyclothiazide Action Pathway;Hydroflumethiazide Action Pathway;Chlorothiazide Action Pathway;NHR;Preimplantation Embryo;ACE Inhibitor Pathway;Gene expression (Transcription);Generic Transcription Pathway;HSP90 chaperone cycle for steroid hormone receptors (SHR);Cellular responses to stress;Nuclear Receptor transcription pathway;RNA Polymerase II Transcription;Cellular responses to external stimuli (Consensus)

Recessive Scores

• pRec: 0.502

Intolerance Scores

• loftool: 0.0298
• rvis_EVS: -0.35
• rvis_percentile_EVS: 29.49

Haploinsufficiency Scores

• pHI: 0.294
• hipred: Y
• hipred_score: 0.636
• ghis: 0.506

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.996

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Nr3c2
• Phenotype: behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); hematopoietic system phenotype; cardiovascular system phenotype (the observable morphological and physiological characteristics of the mammalian heart, blood vessels, or circulatory system that are manifested through development and lifespan); 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); nervous system phenotype (the observable morphological and physiological characteristics of the extensive, intricate network of electochemical structures in the body that is comprised of the brain, spinal cord, nerves, ganglia and parts of the receptor organs that are manifested through development and lifespan); renal/urinary system phenotype; homeostasis/metabolism phenotype; cellular phenotype; growth/size/body region phenotype; muscle phenotype

Gene ontology

• Biological process: regulation of transcription by RNA polymerase II;transcription initiation from RNA polymerase II promoter;signal transduction;steroid hormone mediated signaling pathway
• Cellular component: nucleoplasm;endoplasmic reticulum membrane;cytosol;receptor complex
• Molecular function: DNA-binding transcription factor activity, RNA polymerase II-specific;DNA-binding transcription factor activity;steroid hormone receptor activity;steroid binding;protein binding;zinc ion binding;sequence-specific DNA binding