FZD2

protein-coding

frizzled class receptor 2, the group of G protein-coupled receptors, Class F frizzled

Gene summary

This intronless gene is a member of the frizzled gene family. Members of this family encode seven-transmembrane domain proteins that are receptors for the wingless type MMTV integration site family of signaling proteins. This gene encodes a protein that is coupled to the beta-catenin canonical signaling pathway. Competition between the wingless-type MMTV integration site family, member 3A and wingless-type MMTV integration site family, member 5A gene products for binding of this protein is thought to regulate the beta-catenin-dependent and -independent pathways. [provided by RefSeq, Dec 2010]

MANE transcript

NM_001466.4

Inheritance

ClinVar variants

P:11U:163B:71

Top phenotype

Omodysplasia 2

gnomAD constraint

pLI —, LoF o/e 0.18

Max pathogenic AF

—

Genomic locus

chr17:44,557,484-44,561,262

External References & Databases

Ensembl (ENSG00000180340)

Transcript & Mutation Effects

hg38 • Region Span ~3.8 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant omodysplasiaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008123

Submitter: Ambry Genetics

autosomal dominant omodysplasiaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008123

Submitter: Orphanet

autosomal dominant omodysplasiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008123

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant omodysplasiaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0008123

Submitter: PanelApp Australia

autosomal dominant Robinow syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008389

Submitter: Orphanet

Clinical Genomic Database (CGD)

Omodysplasia 2AD

Manifestation: Craniofacial; Genitourinary; Musculoskeletal

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

Refs: 25759469

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FZD2 variants in ClinVar

10 Conditions Cataloged

not providedTotal: 186

not specifiedTotal: 76

FZD2-related disorderTotal: 15

Autosomal dominant omodysplasiaTotal: 12

Autosomal dominant Robinow syndrome 2Total: 4

Autosomal dominant Robinow syndrome 1Total: 3

Short statureTotal: 2

KeratoconusTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001466.4. 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			18 clinvar	49 clinvar	9 clinvar	76
missense		5 clinvar	138 clinvar	10 clinvar	3 clinvar	156
nonsense	2 clinvar	2 clinvar	3 clinvar			7
start loss			1 clinvar			1
frameshift	1 clinvar	1 clinvar	3 clinvar			5
splice donor/acceptor (+/-2bp)						0
Total	3	8	163	59	12	245

Highest pathogenic variant AF is 6.8411714e-7

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 2 of 2 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001466.4	RefSeq	NP_001457.1	1	MANE Select
ENST00000315323.5	Ensembl	ENSP00000323901.3	1	MANE Select

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
fzd2	Danio rerio	Structure: dorsal fin Quality: decreased size abnormal

Gene / Model

Organism

Observed Phenotype

fzd2

Danio rerio

Structure: dorsal fin

Quality: decreased size

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Gastric cancer - Homo sapiens (human)
mTOR signaling pathway - Homo sapiens (human)
Cushing,s syndrome - Homo sapiens (human)
Breast cancer - Homo sapiens (human)
HTLV-I infection - Homo sapiens (human)

Biological Process

membranous septum morphogenesis
muscular septum morphogenesis
outflow tract morphogenesis
G protein-coupled receptor signaling pathway
Wnt signaling pathway, calcium modulating pathway

Molecular Function

G protein-coupled receptor activity
protein binding
Wnt-protein binding
PDZ domain binding
Wnt-activated receptor activity

Cellular Component

cytoplasm
plasma membrane
focal adhesion
integral component of membrane
clathrin-coated endocytic vesicle membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000315323
Coding exons: 1
Length: 1983
Individuals with no LoFs: 0
Homozygous LoFs: 0
Heterozygous LoFs: 0
Defined: 0
p: 0.00

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	3.67	165	361	0.457	0.0000203	3638
Missense (PolyPhen)		30	137.11	0.2188		1396
Synonymous	1.81	137	167	0.822	0.0000101	1201
Loss of Function	3.08	3	16.5	0.182	7.11e-7	162

Population LoF Frequency

Population	CAF	p-value	Status
African	0	0.0	absent
Latino/Admixed American	0	0.0	absent
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0	0.0	absent
South Asian	0	0.0	absent
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which leads to the activation of disheveled proteins, inhibition of GSK- 3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues.;

Recessive Scores

pRec: 0.221

Intolerance Scores

LoFtool: 0.0748
RVIS EVS: 0.48
RVIS percentile EVS: 79.25

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): H
Indispensability pred.: E
Indispensability score: 0.855

Gene Damage Prediction

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