ESR2

protein-coding

estrogen receptor 2, the group of Estrogen receptors

Gene summary

This gene encodes a member of the family of estrogen receptors and superfamily of nuclear receptor transcription factors. The gene product contains an N-terminal DNA binding domain and C-terminal ligand binding domain and is localized to the nucleus, cytoplasm, and mitochondria. Upon binding to 17beta-estradiol or related ligands, the encoded protein forms homo- or hetero-dimers that interact with specific DNA sequences to activate transcription. Some isoforms dominantly inhibit the activity of other estrogen receptor family members. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been fully characterized. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001437.3

Inheritance

AR, AD

ClinVar variants

P:1U:104B:54

Top phenotype

Ovarian dysgenesis 8

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr14:64,084,232-64,338,112

External References & Databases

Ensembl (ENSG00000140009)

Transcript & Mutation Effects

hg38 • Region Span ~253.9 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ovarian dysgenesis 8LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032590

Submitter: PanelApp Australia

ovarian dysgenesis 8LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0032590

Submitter: Ambry Genetics

familial medullary thyroid carcinomaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007958

Submitter: Orphanet

male infertility with azoospermia or oligozoospermia due to single gene mutationMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0018393

Submitter: King Faisal Specialist Hospital and Research Center

Alhathal et al., 2020 (PMID: 32719396) reported a missense variant in a large male infertility cohort (n=285 infertile man and case–control fertile man). Gene is scored according to ClinGen classification. Moderate with total score of 8. Single-variant analysis (3 points), experimental evidence: Animal model (4 points) (PMID: 32703416; PMID: 18268329) and testicular expression (1 points) (PMID: 33163677 ).

ovarian dysgenesis 8LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032590

Submitter: Labcorp Genetics (formerly Invitae)

ovarian dysgenesis 8MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0032590

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Ovarian dysgenesis 8AR

Manifestation: Endocrine; Obstetric

Intervention: Endocrine

Rationale: Individuals can present with features such as primary amenorrhea, and osteoporosis, and medical management (eg, with estrogen therapy) has been described as beneficial

Refs: 30113650

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ESR2 variants in ClinVar

5 Conditions Cataloged

not providedTotal: 104

not specifiedTotal: 82

ESR2-related disorderTotal: 15

Ovarian dysgenesis 8Total: 4

Familial medullary thyroid carcinomaTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001437.3. 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			2 clinvar	31 clinvar	8 clinvar	41
missense	1 clinvar		93 clinvar	14 clinvar	1 clinvar	109
nonsense			3 clinvar			3
start loss						0
frameshift			5 clinvar			5
splice donor/acceptor (+/-2bp)			1 clinvar			1
Total	1	0	104	45	9	159

Highest pathogenic variant AF is 0.0000014588339

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001437.3	RefSeq	NP_001428.1	8	MANE Select
ENST00000341099.6	Ensembl	ENSP00000343925.4	8	MANE Select
NM_001040275.1	RefSeq	NP_001035365.1	8	Standard
NM_001214902.1	RefSeq	NP_001201831.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
esr2a	Danio rerio	Structure: subintestinal vein Quality: aplastic abnormal

Gene / Model

Organism

Observed Phenotype

esr2a

Danio rerio

Structure: subintestinal vein

Quality: aplastic

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Breast cancer - Homo sapiens (human)
Estrogen signaling pathway - Homo sapiens (human)
Prolactin signaling pathway - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Aromatase Inhibitor Pathway (Breast Cell), Pharmacodynamics

Biological Process

negative regulation of transcription by RNA polymerase II
regulation of transcription, DNA-templated
transcription initiation from RNA polymerase II promoter
signal transduction
cell-cell signaling

Molecular Function

RNA polymerase II proximal promoter sequence-specific DNA binding
DNA-binding transcription factor activity, RNA polymerase II-specific
DNA binding
DNA-binding transcription factor activity
steroid hormone receptor activity

Cellular Component

extracellular region
nucleus
nucleoplasm
mitochondrion

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000341099
Coding exons: 8
Length: 253881
Individuals with no LoFs: 125628
Homozygous LoFs: 0
Heterozygous LoFs: 119
Defined: 125747
p: 0.000473

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.405	304	325	0.937	0.0000196	3477
Missense (PolyPhen)		78	94.441	0.82591		1073
Synonymous	-2.64	169	131	1.29	0.00000858	1036
Loss of Function	1.53	15	22.9	0.654	0.00000120	267

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00025	0.00025	rare
Latino/Admixed American	0.00032	0.00032	rare
Ashkenazi Jewish	0.0012	0.0012	notable
East Asian	0.0010	0.0010	notable
Finnish	0.00019	0.00018	rare
European (Non-Finnish)	0.00043	0.00042	rare
South Asian	0.00070	0.00069	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Nuclear hormone receptor. Binds estrogens with an affinity similar to that of ESR1, and activates expression of reporter genes containing estrogen response elements (ERE) in an estrogen-dependent manner (PubMed:20074560). Isoform beta-cx lacks ligand binding ability and has no or only very low ere binding activity resulting in the loss of ligand-dependent transactivation ability. DNA-binding by ESR1 and ESR2 is rapidly lost at 37 degrees Celsius in the absence of ligand while in the presence of 17 beta-estradiol and 4-hydroxy-tamoxifen loss in DNA-binding at elevated temperature is more gradual. {ECO:0000269|PubMed:20074560}.;

Recessive Scores

pRec: 0.749

Intolerance Scores

LoFtool: 0.0411
RVIS EVS: -0.95
RVIS percentile EVS: 9.27

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.897

Gene Damage Prediction

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