NR2F2

protein-coding

nuclear receptor subfamily 2 group F member 2, the group of Nuclear receptor subfamily 2 group F|MicroRNA protein coding host genes

Gene summary

This gene encodes a member of the steroid thyroid hormone superfamily of nuclear receptors. The encoded protein is a ligand inducible transcription factor that is involved in the regulation of many different genes. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

Previous symbols:

ARP1
TFCOUP2

MANE transcript

NM_021005.4

Inheritance

ClinVar variants

P:42U:89B:52

Top phenotype

Congenital heart defects, multiple types, 4; 46 XX sex reversal 5

gnomAD constraint

pLI —, LoF o/e 0

Max pathogenic AF

—

Genomic locus

chr15:96,325,938-96,340,263

External References & Databases

Ensembl (ENSG00000185551)

Transcript & Mutation Effects

hg38 • Region Span ~14.3 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

syndromic diseaseSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0002254

Submitter: PanelApp Australia

NR2F2 related multiple congenital anomalies/dysmorphic syndromeDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0800458

Submitter: ClinGen

NR2F2 was first reported in relation to autosomal dominant multiple congenital anomalies/dysmorphic syndrome-NR2F2 in 2014 (Al Turk et al., PMID:24702954). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in the molecular mechanisms, and phenotypic variability. Therefore, the following disease entities have been split into separate entities: 46XX sex reversal 5 (OMIM:618901), Congenital heart defects, multiple types, 4 (OMIM: 615779). Nine unique variants (missense, nonsense, frameshift, splice acceptor) and seven of which were de novo that have been reported in ten probands in five publications (PMIDs: 24702954, 27363585, 29663647, 29222010, 37500725) are included in this curation.Two of the variants were found to segregated respectively in two separate families (PMID:24702954, 29222010). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. This gene-disease relationship is also supported by a mouse model, and expression data (PMIDs: 10215630, 24702954). In summary, NR2F2 is definitively associated with autosomal dominant multiple congenital anomalies/dysmorphic syndrome-NR2F2. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Congenital Heart Disease GCEP on the meeting date 8/1/2023 (SOP Version 9).

congenital heart defects, multiple types, 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014344

Submitter: Labcorp Genetics (formerly Invitae)

congenital heart defects, multiple types, 4MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014344

Submitter: Ambry Genetics

46,xx sex reversal 5DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0030049

Submitter: G2P

Clinical Genomic Database (CGD)

Congenital heart defects, multiple types, 4; 46 XX sex reversal 5AD

Manifestation: Cardiovascular; Craniofacial; Endocrine; Genitourinary; Ophthalmologic

Intervention: Cardiovascular

Rationale: The conditions can involve congenital cardiac anomalies, and awareness may allow early management

Refs: 18371933; 24702954; 29478779; 31687637

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NR2F2 variants in ClinVar

14 Conditions Cataloged

Congenital heart defects, multiple types, 4Total: 88

not providedTotal: 50

Inborn genetic diseasesTotal: 28

NR2F2-related disorderTotal: 18

not specifiedTotal: 13

NR2F2 associated disordersTotal: 7

46,xx sex reversal 5Total: 5

Neurodevelopmental disorderTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_021005.4. 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		47 clinvar	1 clinvar	49
missense	3 clinvar	8 clinvar	88 clinvar	4 clinvar		103
nonsense	7 clinvar	2 clinvar	1 clinvar			10
start loss						0
frameshift	9 clinvar	9 clinvar				18
splice donor/acceptor (+/-2bp)	3 clinvar					3
Total	22	20	89	51	1	183

Highest pathogenic variant AF is 6.1957945e-7

Loading ClinVar variants...

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_021005.4	RefSeq	NP_066285.1	3	MANE Select
ENST00000394166.8	Ensembl	ENSP00000377721.3	3	MANE Select
NM_001145155.2	RefSeq	NP_001138627.1	3	Standard
NM_001145156.1	RefSeq	NP_001138628.1	2	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
nr2f2	Danio rerio	Structure: thoracic duct Quality: immature abnormal

Gene / Model

Organism

Observed Phenotype

nr2f2

Danio rerio

Structure: thoracic duct

Quality: immature

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

NHR
Nuclear Receptors
White fat cell differentiation
Ectoderm Differentiation
White fat cell differentiation

Biological Process

negative regulation of transcription by RNA polymerase II
neuron migration
maternal placenta development
negative regulation of endothelial cell proliferation
positive regulation of systemic arterial blood pressure

Molecular Function

DNA-binding transcription factor activity, RNA polymerase II-specific
retinoic acid binding
DNA-binding transcription factor activity
steroid hormone receptor activity
transcription corepressor activity

Cellular Component

nucleus
nucleoplasm
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000394166
Coding exons: 3
Length: 14326
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.60	79	234	0.338	0.0000126	2705
Missense (PolyPhen)		15	105.28	0.14248		1142
Synonymous	-2.38	132	101	1.30	0.00000591	838
Loss of Function	3.44	0	13.8	0.00	5.95e-7	155

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Ligand-activated transcription factor. Activated by high concentrations of 9-cis-retinoic acid and all-trans-retinoic acid, but not by dexamethasone, cortisol or progesterone (in vitro). Regulation of the apolipoprotein A-I gene transcription. Binds to DNA site A. {ECO:0000269|PubMed:18798693, ECO:0000269|PubMed:1899293, ECO:0000269|PubMed:9343308}.;

Recessive Scores

pRec: 0.292

Intolerance Scores

RVIS EVS: -0.41
RVIS percentile EVS: 26.23

Essentials

Essential (CRISPR): N
Essential (CRISPR2): S
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.944

Gene Damage Prediction

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