EMP2

protein-coding

epithelial membrane protein 2

Gene summary

This gene encodes a tetraspan protein of the PMP22/EMP family. The encoded protein regulates cell membrane composition. It has been associated with various functions including endocytosis, cell signaling, cell proliferation, cell migration, cell adhesion, cell death, cholesterol homeostasis, urinary albumin excretion, and embryo implantation. It is known to negatively regulate caveolin-1, a scaffolding protein which is the main component of the caveolae plasma membrane invaginations found in most cell types. Through activation of PTK2 it positively regulates vascular endothelial growth factor A. It also modulates the function of specific integrin isomers in the plasma membrane. Up-regulation of this gene has been linked to cancer progression in multiple different tissues. Mutations in this gene have been associated with nephrotic syndrome type 10 (NPHS10). [provided by RefSeq, Mar 2015]

MANE transcript

NM_001424.6

Inheritance

AR, AD

ClinVar variants

P:3U:44B:26

Top phenotype

Nephrotic syndrome, type 10

gnomAD constraint

pLI —, LoF o/e 1.29

Max pathogenic AF

—

Genomic locus

chr16:10,528,422-10,580,632

External References & Databases

Ensembl (ENSG00000213853)

Transcript & Mutation Effects

hg38 • Region Span ~52.2 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nephrotic syndrome, type 10LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014373

Submitter: Ambry Genetics

nephrotic syndrome, type 10STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014373

Submitter: Labcorp Genetics (formerly Invitae)

familial idiopathic steroid-resistant nephrotic syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019006

Submitter: Orphanet

nephrotic syndrome, type 10MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014373

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Nephrotic syndrome, type 10AR

Manifestation: Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: Management with cyclophosphamide has been described as beneficial (frequent relapses have been described with steroid treatment)

Refs: 24814193

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to EMP2 variants in ClinVar

4 Conditions Cataloged

not providedTotal: 52

not specifiedTotal: 38

EMP2-related disorderTotal: 9

Nephrotic syndrome, type 10Total: 8

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001424.6. 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				21 clinvar	2 clinvar	23
missense	1 clinvar		40 clinvar	3 clinvar		44
nonsense		1 clinvar	2 clinvar			3
start loss						0
frameshift						0
splice donor/acceptor (+/-2bp)		1 clinvar	2 clinvar			3
Total	1	2	44	24	2	73

Highest pathogenic variant AF is 0.000032840195

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_001424.6	RefSeq	NP_001415.1	4	MANE Select
ENST00000359543.8	Ensembl	ENSP00000352540.3	4	MANE Select
ENST00000536829.1	Ensembl	ENSP00000445712.1	4	Standard
ENST00000536829.2	Ensembl	ENSP00000445712.1	4	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
emp2	Danio rerio	Structure: orbit Quality: edematous abnormal

Gene / Model

Organism

Observed Phenotype

emp2

Danio rerio

Structure: orbit

Quality: edematous

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Biological Process

membrane raft assembly
T cell mediated cytotoxicity
regulation of cell-matrix adhesion
positive regulation of cell-matrix adhesion
regulation of glomerular filtration

Molecular Function

integrin binding
protein binding
kinase binding
protein kinase binding

Cellular Component

Golgi membrane
nucleus
cytoplasm
Golgi apparatus
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000359543
Coding exons: 4
Length: 52277
Individuals with no LoFs: 125723
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125746
p: 0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.440	118	105	1.12	0.00000644	1106
Missense (PolyPhen)		50	44.508	1.1234		509
Synonymous	-0.139	45	43.8	1.03	0.00000316	314
Loss of Function	-0.703	9	6.99	1.29	2.98e-7	78

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.00017	0.00017	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00011	0.00011	rare
South Asian	0.000070	0.000065	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions as a key regulator of cell membrane composition by regulating proteins surface expression. Also, plays a role in regulation of processes including cell migration, cell proliferation, cell contraction and cell adhesion. Negatively regulates caveolae formation by reducing CAV1 expression and CAV1 amount by increasing lysosomal degradation (PubMed:24814193). Facilitates surface trafficking and formation of lipid rafts bearing GPI-anchor proteins (By similarity). Regulates surface expression of MHC1 and ICAM1 proteins increasing susceptibility to T-cell mediated cytotoxicity (By similarity). Regulates the plasma membrane expression of the integrin heterodimers ITGA6-ITGB1, ITGA5-ITGB3 and ITGA5-ITGB1 resulting in modulation of cell-matrix adhesion (PubMed:16216233). Also regulates many processes through PTK2. Regulates blood vessel endothelial cell migration and angiogenesis by regulating VEGF protein expression through PTK2 activation (PubMed:23439602). Regulates cell migration and cell contraction through PTK2 and SRC activation (PubMed:21637765, PubMed:22728127). Regulates focal adhesion density, F-actin conformation and cell adhesion capacity through interaction with PTK2 (PubMed:19494199). Positively regulates cell proliferation (PubMed:24814193). Plays a role during cell death and cell blebbing (PubMed:12107182). Promotes angiogenesis and vasculogenesis through induction of VEGFA via a HIF1A-dependent pathway (PubMed:23334331). Also plays a role in embryo implantation by regulating surface trafficking of integrin heterodimer ITGA5-ITGB3 (PubMed:16487956). May play a role in glomerular filtration (By similarity). {ECO:0000250|UniProtKB:F1QIK8, ECO:0000250|UniProtKB:O88662, ECO:0000269|PubMed:12107182, ECO:0000269|PubMed:16216233, ECO:0000269|PubMed:16487956, ECO:0000269|PubMed:19494199, ECO:0000269|PubMed:21637765, ECO:0000269|PubMed:22728127, ECO:0000269|PubMed:23334331, ECO:0000269|PubMed:23439602, ECO:0000269|PubMed:24814193}.;
Disease: DISEASE: Nephrotic syndrome 10 (NPHS10) [MIM:615861]: A form of nephrotic syndrome, a renal disease clinically characterized by focal segmental glomerulosclerosis, progressive renal failure, severe proteinuria, hypoalbuminemia, hyperlipidemia and edema. NPHS10 is a steroid-sensitive form characterized by onset in childhood and remission without end-stage kidney disease. {ECO:0000269|PubMed:24814193}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Intolerance Scores

LoFtool: 0.300
RVIS EVS: -0.36
RVIS percentile EVS: 28.93

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.645

Gene Damage Prediction

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