ESR2

estrogen receptor 2, the group of Estrogen receptors

Basic information

Region (hg38): 14:64084232-64338112

Links

ENSG00000140009 ∙ NCBI:2100 ∙ OMIM:601663 ∙ HGNC:3468 ∙ Uniprot:Q92731 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• ovarian dysgenesis 8 (Limited), mode of inheritance: AD
• male infertility with azoospermia or oligozoospermia due to single gene mutation (Moderate), mode of inheritance: AR
• familial medullary thyroid carcinoma (Supportive), mode of inheritance: AD
• ovarian dysgenesis 8 (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Ovarian dysgenesis 8	AR	Endocrine	Individuals can present with features such as primary amenorrhea, and osteoporosis, and medical management (eg, with estrogen therapy) has been described as beneficial	Endocrine; Obstetric	30113650

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ESR2 gene.

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ESR2 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			2	28	8	38
missense			49	10	3	62
nonsense						0
start loss						0
frameshift			2			2
inframe indel			1			1
splice donor/acceptor (+/-2bp)						0
splice region				2		2
non coding				5	23	28
Total	0	0	54	43	34

Variants in ESR2

This is a list of pathogenic ClinVar variants found in the ESR2 region.

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

Position	Type	Phenotype	Significance	ClinVar
14-64087370-G-A			Benign (Jul 15, 2018)
14-64087548-G-A			Benign (Jul 09, 2018)
14-64087671-A-G		not specified	Uncertain significance (Feb 14, 2023)
14-64087674-G-T		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Uncertain significance (Jun 27, 2022)
14-64087676-T-C		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Likely benign (Jul 22, 2020)
14-64087683-GA-G		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Uncertain significance (Feb 24, 2020)
14-64087694-G-C		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Uncertain significance (Aug 09, 2022)
14-64087714-C-T		Emery-Dreifuss muscular dystrophy 5, autosomal dominant • not specified	Conflicting classifications of pathogenicity (Nov 22, 2023)
14-64087716-A-G		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Benign/Likely benign (Jan 18, 2024)
14-64087717-T-A		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Uncertain significance (Nov 06, 2023)
14-64087725-G-A		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Uncertain significance (Jul 19, 2022)
14-64087731-G-A		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Uncertain significance (Apr 26, 2023)
14-64087735-A-G		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Likely benign (Jan 12, 2018)
14-64087735-AC-GA		not specified • Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Conflicting classifications of pathogenicity (Jul 05, 2024)
14-64087736-C-A		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Likely benign (Jan 13, 2018)
14-64087736-C-T		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Likely benign (Nov 18, 2023)
14-64087743-A-G		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Uncertain significance (Dec 07, 2022)
14-64087772-A-G		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Likely benign (Oct 21, 2020)
14-64087773-TC-T		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Likely benign (Mar 11, 2022)
14-64087778-A-G		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Uncertain significance (Oct 17, 2022)
14-64087794-C-G		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Uncertain significance (Apr 05, 2023)
14-64087795-A-G		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Uncertain significance (Jun 13, 2022)
14-64087799-A-G		not specified • Emery-Dreifuss muscular dystrophy 5, autosomal dominant • SYNE2-related disorder	Benign (Feb 01, 2024)
14-64087801-C-T		Emery-Dreifuss muscular dystrophy 5, autosomal dominant	Uncertain significance (Oct 26, 2018)
14-64087823-G-C		Emery-Dreifuss muscular dystrophy 5, autosomal dominant • not specified	Uncertain significance (Jun 30, 2023)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ESR2	protein_coding	protein_coding	ENST00000341099	8	253881

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
4.45e-8	0.830	125628	0	119	125747	0.000473

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	0.405	304	325	0.937	0.0000196	3477
Missense in 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

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000565	0.000564
Ashkenazi Jewish	0.00119	0.00119
East Asian	0.00103	0.00103
Finnish	0.000185	0.000185
European (Non-Finnish)	0.000428	0.000422
Middle Eastern	0.00103	0.00103
South Asian	0.000695	0.000686
Other	0.00	0.00

dbNSFP

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}.
• Pathway: 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;NHR;Nuclear Receptors;Ovarian Infertility Genes;Sudden Infant Death Syndrome (SIDS) Susceptibility Pathways;Disease;Signal Transduction;Gene expression (Transcription);Generic Transcription Pathway;Nuclear Receptor transcription pathway;RNA Polymerase II Transcription;PIP3 activates AKT signaling;Signaling by Nuclear Receptors;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;Constitutive Signaling by Aberrant PI3K in Cancer;PI3K/AKT Signaling in Cancer;ESR-mediated signaling;Intracellular signaling by second messengers;Diseases of signal transduction;Validated nuclear estrogen receptor alpha network;Plasma membrane estrogen receptor signaling;Validated nuclear estrogen receptor beta network (Consensus)

Recessive Scores

• pRec: 0.749

Intolerance Scores

• loftool: 0.0411
• rvis_EVS: -0.95
• rvis_percentile_EVS: 9.27

Haploinsufficiency Scores

• pHI: 0.293
• hipred: Y
• hipred_score: 0.564
• ghis: 0.397

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.897

Gene Damage Prediction

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

Mouse Genome Informatics

• Gene name: Esr2
• Phenotype: integument phenotype (the observable morphological and physiological characteristics of the skin and its associated structures, such as the hair, nails, sweat glands, sebaceous glands and other secretory glands that are manifested through development and lifespan); growth/size/body region phenotype; adipose tissue phenotype (the observable morphological and physiological characteristics of mammalian fat tissue that are manifested through development and lifespan); endocrine/exocrine gland phenotype; muscle phenotype; cellular phenotype; homeostasis/metabolism phenotype; skeleton phenotype; renal/urinary system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); liver/biliary system phenotype; respiratory system phenotype; normal 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); reproductive system phenotype; 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); neoplasm; limbs/digits/tail phenotype; 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); hearing/vestibular/ear phenotype; digestive/alimentary phenotype; immune system phenotype

Zebrafish Information Network

• Gene name: esr2a
• Affected structure: subintestinal vein
• Phenotype tag: abnormal
• Phenotype quality: aplastic

Gene ontology

• 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;negative regulation of cell growth;intracellular estrogen receptor signaling pathway;positive regulation of transcription, DNA-templated;positive regulation of DNA-binding transcription factor activity;extracellular negative regulation of signal transduction
• Cellular component: extracellular region;nucleus;nucleoplasm;mitochondrion
• 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;transcription coactivator activity;nuclear receptor activity;steroid binding;protein binding;zinc ion binding;enzyme binding;estrogen receptor activity;estrogen response element binding;identical protein binding;receptor antagonist activity