PREX2

protein-coding

phosphatidylinositol-3,4,5-trisphosphate dependent Rac exchange factor 2, the group of Dbl family Rho GEFs|Protein phosphatase 1 regulatory subunits|PDZ domain containing

Gene summary

The protein encoded by this gene belongs to the phosphatidylinositol 3,4,5-trisphosphate (PIP3)-dependent Rac exchanger (PREX) family, which are Dbl-type guanine-nucleotide exchange factors for Rac family small G proteins. Structural domains of this protein include the catalytic diffuse B-cell lymphoma homology and pleckstrin homology (DHPH) domain, two disheveled, EGL-10, and pleckstrin homology (DEP) domains, two PDZ domains, and a C-terminal inositol polyphosphate-4 phosphatase (IP4P) domain that is found in one of the isoforms. This protein facilitates the exchange of GDP for GTP on Rac1, allowing the GTP-bound Rac1 to activate downstream effectors. Studies also show that the pleckstrin homology domain of this protein interacts with the phosphatase and tensin homolog (PTEN) gene product to inhibit PTEN phosphatase activity, thus activating the phosphoinositide-3 kinase (PI3K) signaling pathway. Conversely, the PTEN gene product has also been shown to inhibit the GEF activity of this protein. This gene plays a role in insulin-signaling pathways, and either mutations or overexpression of this gene have been observed in some cancers. [provided by RefSeq, Apr 2016]

Previous symbols:

DEPDC2

MANE transcript

NM_024870.4

Inheritance

—

ClinVar variants

P:1U:171B:27

Top phenotype

PREX2-related disorder

gnomAD constraint

pLI —, LoF o/e 0.47

Max pathogenic AF

—

Genomic locus

chr8:67,952,046-68,237,032

External References & Databases

Ensembl (ENSG00000046889)

Transcript & Mutation Effects

hg38 • Region Span ~285.0 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

No GenCC data available for this gene.

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PREX2 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 152

PREX2-related disorderTotal: 30

not providedTotal: 15

Prostate cancerTotal: 1

Cerebral arteriovenous malformationTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024870.4. 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			3 clinvar	13 clinvar	3 clinvar	19
missense		1 clinvar	161 clinvar	5 clinvar	6 clinvar	173
nonsense			2 clinvar			2
start loss						0
frameshift			1 clinvar			1
splice donor/acceptor (+/-2bp)			4 clinvar			4
Total	0	1	171	18	9	199

Highest pathogenic variant AF is 0.000022308592

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 12 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_024870.4	RefSeq	NP_079146.2	40	MANE Select
ENST00000288368.5	Ensembl	ENSP00000288368.4	40	MANE Select
NM_025170.6	RefSeq	NP_079446.3	24	Standard
ENST00000854544.1	Ensembl	ENSP00000524603.1	38	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Signal Transduction
Regulation of PTEN stability and activity
Regulation of RAC1 activity
PTEN Regulation
PIP3 activates AKT signaling

Biological Process

G protein-coupled receptor signaling pathway
adult locomotory behavior
phosphatidylinositol 3-kinase signaling
regulation of Rho protein signal transduction
positive regulation of GTPase activity

Molecular Function

GTPase activator activity
Rac guanyl-nucleotide exchange factor activity

Cellular Component

cytosol
plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000288368
Coding exons: 40
Length: 284913
Individuals with no LoFs: 125531
Homozygous LoFs: 1
Heterozygous LoFs: 216
Defined: 125748
p: 0.000863

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.73	719	862	0.834	0.0000454	10632
Missense (PolyPhen)		300	376.21	0.79742		4618
Synonymous	-0.344	307	299	1.03	0.0000157	2884
Loss of Function	4.57	41	87.0	0.471	0.00000403	1134

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0025	0.0025	notable
Latino/Admixed American	0.0012	0.0012	notable
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00022	0.00022	rare
Finnish	0.0033	0.0032	notable
European (Non-Finnish)	0.00037	0.00036	rare
South Asian	0.00039	0.00039	rare
Other	0.0012	0.0011	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Functions as a RAC1 guanine nucleotide exchange factor (GEF), activating Rac proteins by exchanging bound GDP for free GTP. Its activity is synergistically activated by phosphatidylinositol 3,4,5-trisphosphate and the beta gamma subunits of heterotrimeric G protein. Mediates the activation of RAC1 in a PI3K-dependent manner. May be an important mediator of Rac signaling, acting directly downstream of both G protein- coupled receptors and phosphoinositide 3-kinase. {ECO:0000269|PubMed:15304342, ECO:0000269|PubMed:15304343, ECO:0000269|PubMed:15897194}.;

Recessive Scores

pRec: 0.103

Intolerance Scores

LoFtool: 0.582
RVIS EVS: -0.67
RVIS percentile EVS: 15.42

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.186

Gene Damage Prediction

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