ERBB2

erb-b2 receptor tyrosine kinase 2, the group of CD molecules|Minor histocompatibility antigens|Erb-b2 receptor tyrosine kinases|MicroRNA protein coding host genes

Basic information

Region (hg38): 17:39687914-39730426

Previous symbols: [ "NGL" ]

Links

ENSG00000141736 ∙ NCBI:2064 ∙ OMIM:164870 ∙ HGNC:3430 ∙ Uniprot:P04626 ∙ AlphaFold ∙ GenCC ∙ jax ∙ Sfari ∙ GnomAD ∙ Pubmed ∙ ClinVar

Phenotypes

GenCC

Source: genCC

• lung cancer (Limited), mode of inheritance: AD
• Hirschsprung disease (Supportive), mode of inheritance: AD
• glioma susceptibility 1 (Limited), mode of inheritance: Unknown
• visceral neuropathy, familial, 2, autosomal recessive (Limited), mode of inheritance: Unknown

Clinical Genomic Database

Source: CGD

Condition	Inheritance	Intervention Categories	Intervention/Rationale	Manifestation Categories	References
Visceral neuropathy, familial, 2, autosomal recessive	AR	Audiologic/Otolaryngologic	Early recognition and treatment of hearing impairment may improve outcomes, including speech and language development	Audiologic/Otolaryngologic; Gastrointestinal; Neurologic	33497358

ClinVar

This is a list of variants' phenotypes submitted to ClinVar and linked to the ERBB2 gene.

• Lung adenocarcinoma (2 variants)
• Neoplasm (1 variants)
• Squamous cell carcinoma of the head and neck (1 variants)
• Ovarian serous cystadenocarcinoma (1 variants)
• Transitional cell carcinoma of the bladder (1 variants)
• Squamous cell carcinoma of the skin (1 variants)
• Neoplasm of uterine cervix (1 variants)
• not provided (1 variants)
• Non-small cell lung carcinoma (1 variants)
• Neoplasm of the large intestine (1 variants)
• Gastric adenocarcinoma (1 variants)
• Breast neoplasm (1 variants)

Variants pathogenicity by type

Statistics on ClinVar variants can assist in determining whether a specific variant type in the ERBB2 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			6	163	18	187
missense	1		261	11	7	280
nonsense			8			8
start loss			1	1		2
frameshift		1	5			6
inframe indel	1	8	1			10
splice donor/acceptor (+/-2bp)			3		1	4
splice region			12	35	4	51
non coding			3	76	6	85
Total	2	9	288	251	32

Variants in ERBB2

This is a list of pathogenic ClinVar variants found in the ERBB2 region.

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

Position	Type	Phenotype	Significance	ClinVar
17-39687915-G-A			Likely benign (Oct 05, 2023)
17-39687933-C-CCGGCTCA		Hyperphosphatasia with intellectual disability syndrome 4	Pathogenic (Sep 22, 2020)
17-39687941-C-G			Uncertain significance (Apr 30, 2020)
17-39687946-G-A			Likely benign (Nov 27, 2023)
17-39687961-C-T			Likely benign (Oct 22, 2023)
17-39687963-CCA-G		Hyperphosphatasia with intellectual disability syndrome 4	Likely pathogenic (Jun 03, 2021)
17-39687971-G-GC		Hyperphosphatasia-intellectual disability syndrome	Likely pathogenic (Aug 01, 2023)
17-39687976-C-A			Likely benign (Feb 23, 2023)
17-39687980-G-T			Uncertain significance (May 15, 2019)
17-39687982-TA-T			Likely pathogenic (Nov 21, 2016)
17-39687985-C-G			Likely benign (Sep 18, 2022)
17-39687988-G-A			Likely benign (Jul 25, 2022)
17-39687991-C-G		Inborn genetic diseases	Uncertain significance (Jul 30, 2023)
17-39687998-G-A		Inborn genetic diseases	Uncertain significance (Sep 23, 2023)
17-39688007-C-T			Likely benign (Aug 22, 2023)
17-39688009-G-A			Likely benign (Aug 08, 2023)
17-39699581-C-A		not specified	not provided (Sep 19, 2013)
17-39700245-C-G			Uncertain significance (Aug 16, 2022)
17-39700248-G-T		not specified	Uncertain significance (Jan 30, 2024)
17-39700253-C-G			Likely benign (Nov 03, 2021)
17-39700277-C-T			Likely benign (Dec 07, 2023)
17-39700279-C-T			Uncertain significance (Apr 01, 2022)
17-39700281-C-T		not specified	Likely benign (Jan 25, 2024)
17-39700289-C-A			Benign (Jan 30, 2024)
17-39700289-C-T			Likely benign (Nov 23, 2020)

GnomAD

Source: gnomAD

Gene	Type	Bio Type	Transcript	Coding Exons	Length
ERBB2	protein_coding	protein_coding	ENST00000269571	27	42513

pLI Probability LOF Intolerant	pRec Probability LOF Recessive	Individuals with no LOFs	Individuals with Homozygous LOFs	Individuals with Heterozygous LOFs	Defined	p
0.00599	0.994	125714	0	34	125748	0.000135

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible in Transcript
Missense	3.25	510	763	0.669	0.0000474	8100
Missense in Polyphen		168	317.38	0.52933		3378
Synonymous	0.154	317	321	0.989	0.0000202	2592
Loss of Function	5.57	18	67.3	0.268	0.00000383	692

LoF frequencies by population

Ethnicity	Sum of pLOFs	p
African & African-American	0.000342	0.000342
Ashkenazi Jewish	0.00	0.00
East Asian	0.000218	0.000217
Finnish	0.00	0.00
European (Non-Finnish)	0.000170	0.000167
Middle Eastern	0.000218	0.000217
South Asian	0.0000996	0.0000980
Other	0.000347	0.000326

dbNSFP

Source: dbNSFP

• Function: FUNCTION: Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding. Essential component of a neuregulin-receptor complex, although neuregulins do not interact with it alone. GP30 is a potential ligand for this receptor. Regulates outgrowth and stabilization of peripheral microtubules (MTs). Upon ERBB2 activation, the MEMO1-RHOA-DIAPH1 signaling pathway elicits the phosphorylation and thus the inhibition of GSK3B at cell membrane. This prevents the phosphorylation of APC and CLASP2, allowing its association with the cell membrane. In turn, membrane-bound APC allows the localization of MACF1 to the cell membrane, which is required for microtubule capture and stabilization. {ECO:0000305}.
• Disease: DISEASE: Glioma (GLM) [MIM:137800]: Gliomas are benign or malignant central nervous system neoplasms derived from glial cells. They comprise astrocytomas and glioblastoma multiforme that are derived from astrocytes, oligodendrogliomas derived from oligodendrocytes and ependymomas derived from ependymocytes. {ECO:0000269|PubMed:15457249}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Ovarian cancer (OC) [MIM:167000]: The term ovarian cancer defines malignancies originating from ovarian tissue. Although many histologic types of ovarian tumors have been described, epithelial ovarian carcinoma is the most common form. Ovarian cancers are often asymptomatic and the recognized signs and symptoms, even of late-stage disease, are vague. Consequently, most patients are diagnosed with advanced disease. {ECO:0000269|PubMed:15457249, ECO:0000269|PubMed:17344846}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Lung cancer (LNCR) [MIM:211980]: A common malignancy affecting tissues of the lung. The most common form of lung cancer is non-small cell lung cancer (NSCLC) that can be divided into 3 major histologic subtypes: squamous cell carcinoma, adenocarcinoma, and large cell lung cancer. NSCLC is often diagnosed at an advanced stage and has a poor prognosis. {ECO:0000269|PubMed:15457249}. Note=The gene represented in this entry is involved in disease pathogenesis.; DISEASE: Gastric cancer (GASC) [MIM:613659]: A malignant disease which starts in the stomach, can spread to the esophagus or the small intestine, and can extend through the stomach wall to nearby lymph nodes and organs. It also can metastasize to other parts of the body. The term gastric cancer or gastric carcinoma refers to adenocarcinoma of the stomach that accounts for most of all gastric malignant tumors. Two main histologic types are recognized, diffuse type and intestinal type carcinomas. Diffuse tumors are poorly differentiated infiltrating lesions, resulting in thickening of the stomach. In contrast, intestinal tumors are usually exophytic, often ulcerating, and associated with intestinal metaplasia of the stomach, most often observed in sporadic disease. {ECO:0000269|PubMed:15457249, ECO:0000269|PubMed:17344846}. Note=The protein represented in this entry is involved in disease pathogenesis.; DISEASE: Note=Chromosomal aberrations involving ERBB2 may be a cause gastric cancer. Deletions within 17q12 region producing fusion transcripts with CDK12, leading to CDK12-ERBB2 fusion leading to truncated CDK12 protein not in-frame with ERBB2. {ECO:0000269|PubMed:21097718}.
• Pathway: PI3K-Akt signaling pathway - Homo sapiens (human);Non-small cell lung cancer - Homo sapiens (human);Gastric cancer - Homo sapiens (human);Focal adhesion - Homo sapiens (human);Central carbon metabolism in cancer - Homo sapiens (human);Adherens junction - Homo sapiens (human);Bladder cancer - Homo sapiens (human);HIF-1 signaling pathway - Homo sapiens (human);Tight junction - Homo sapiens (human);Breast cancer - Homo sapiens (human);ErbB signaling pathway - Homo sapiens (human);Prostate cancer - Homo sapiens (human);Calcium signaling pathway - Homo sapiens (human);MAPK signaling pathway - Homo sapiens (human);Proteoglycans in cancer - Homo sapiens (human);MicroRNAs in cancer - Homo sapiens (human);Pathways in cancer - Homo sapiens (human);Pancreatic cancer - Homo sapiens (human);Endometrial cancer - Homo sapiens (human);EGFR Inhibitor Pathway, Pharmacodynamics;Phosphatidylinositol Phosphate Metabolism;Joubert syndrome;EGF-Core;miR-targeted genes in muscle cell - TarBase;Leptin signaling pathway;Prolactin Signaling Pathway;Signaling Pathways in Glioblastoma;Integrated Lung Cancer Pathway;Bladder Cancer;Extracellular vesicle-mediated signaling in recipient cells;Focal Adhesion;Rac1-Pak1-p38-MMP-2 pathway;Pathways Affected in Adenoid Cystic Carcinoma;Association Between Physico-Chemical Features and Toxicity Associated Pathways;Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors;Endometrial cancer;EGF-EGFR Signaling Pathway;ErbB Signaling Pathway;DNA Damage Response (only ATM dependent);SHC1 events in ERBB2 signaling;Developmental Biology;Signaling by PTK6;Disease;Signal Transduction;Gene expression (Transcription);trefoil factors initiate mucosal healing;role of erbb2 in signal transduction and oncology;Generic Transcription Pathway;Prolactin;ERBB2 Activates PTK6 Signaling;Alpha6Beta4Integrin;RNA Polymerase II Transcription;Oncostatin_M;ErbB4 signaling events;Downregulation of ERBB2:ERBB3 signaling;Downregulation of ERBB2 signaling;EGFR1;Sema4D induced cell migration and growth-cone collapse;Sema4D in semaphorin signaling;RAF/MAP kinase cascade;MAPK1/MAPK3 signaling;MAPK family signaling cascades;Semaphorin interactions;PIP3 activates AKT signaling;GRB2 events in ERBB2 signaling;Signaling by Non-Receptor Tyrosine Kinases;a6b1 and a6b4 Integrin signaling;PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling;Negative regulation of the PI3K/AKT network;TFAP2 (AP-2) family regulates transcription of growth factors and their receptors;Axon guidance;Transcriptional regulation by the AP-2 (TFAP2) family of transcription factors;Leptin;Constitutive Signaling by Aberrant PI3K in Cancer;PI3K events in ERBB2 signaling;PLCG1 events in ERBB2 signaling;GRB7 events in ERBB2 signaling;Signaling by ERBB2;ERBB2 Regulates Cell Motility;PI3K/AKT Signaling in Cancer;IL6;Signaling by Receptor Tyrosine Kinases;ErbB2/ErbB3 signaling events;Intracellular signaling by second messengers;Diseases of signal transduction;Validated targets of C-MYC transcriptional repression;ErbB receptor signaling network (Consensus)

Recessive Scores

• pRec: 0.894

Intolerance Scores

• loftool: 0.149
• rvis_EVS: -0.59
• rvis_percentile_EVS: 18.28

Haploinsufficiency Scores

• pHI: 0.999
• hipred: Y
• hipred_score: 0.765
• ghis: 0.514

Essentials

• essential_gene_CRISPR: N
• essential_gene_CRISPR2: N
• essential_gene_gene_trap: N
• gene_indispensability_pred: E
• gene_indispensability_score: 0.974

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	High	High	High
Primary Immunodeficiency	High	High	High
Cancer	High	High	High

Mouse Genome Informatics

• Gene name: Erbb2
• Phenotype: homeostasis/metabolism phenotype; cellular phenotype; muscle phenotype; craniofacial phenotype; growth/size/body region 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); endocrine/exocrine gland phenotype; respiratory system phenotype; behavior/neurological phenotype (the observable actions or reactions of mammalian organisms that are manifested through development and lifespan); skeleton phenotype; digestive/alimentary 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); limbs/digits/tail 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); normal phenotype; neoplasm; embryo phenotype

Zebrafish Information Network

• Gene name: erbb2
• Affected structure: cardiac muscle cell
• Phenotype tag: abnormal
• Phenotype quality: decreased amount

Gene ontology

• Biological process: MAPK cascade;positive regulation of protein phosphorylation;regulation of transcription by RNA polymerase II;protein phosphorylation;signal transduction;cell surface receptor signaling pathway;enzyme linked receptor protein signaling pathway;transmembrane receptor protein tyrosine kinase signaling pathway;peripheral nervous system development;heart development;neuromuscular junction development;motor neuron axon guidance;cell population proliferation;positive regulation of cell population proliferation;phosphatidylinositol 3-kinase signaling;peptidyl-tyrosine phosphorylation;neuron differentiation;positive regulation of cell growth;regulation of microtubule-based process;negative regulation of immature T cell proliferation in thymus;intracellular signal transduction;ERBB2 signaling pathway;wound healing;myelination;positive regulation of MAP kinase activity;positive regulation of MAPK cascade;positive regulation of GTPase activity;positive regulation of translation;regulation of angiogenesis;positive regulation of cell adhesion;positive regulation of transcription by RNA polymerase I;protein autophosphorylation;phosphatidylinositol phosphorylation;oligodendrocyte differentiation;positive regulation of epithelial cell proliferation;positive regulation of protein kinase B signaling;regulation of ERK1 and ERK2 cascade;cellular response to growth factor stimulus;cellular response to epidermal growth factor stimulus;positive regulation of protein targeting to membrane;negative regulation of ERBB signaling pathway;regulation of cell motility
• Cellular component: nucleus;cytosol;plasma membrane;integral component of plasma membrane;basal plasma membrane;endosome membrane;integral component of membrane;basolateral plasma membrane;apical plasma membrane;myelin sheath;receptor complex;perinuclear region of cytoplasm
• Molecular function: RNA polymerase I core binding;protein tyrosine kinase activity;transmembrane receptor protein tyrosine kinase activity;transmembrane signaling receptor activity;Ras guanyl-nucleotide exchange factor activity;protein binding;ATP binding;protein C-terminus binding;growth factor binding;protein phosphatase binding;identical protein binding;ErbB-3 class receptor binding;phosphatidylinositol-4,5-bisphosphate 3-kinase activity;protein heterodimerization activity;protein dimerization activity