CRB2

protein-coding

crumbs cell polarity complex component 2, the group of Crumbs complex

Gene summary

This gene encodes a member of a family of proteins that are components of the Crumbs cell polarity complex. In mammals, members of this family are thought to play a role in many cellular processes in early embryonic development. A similar protein in Drosophila determines apicobasal polarity in embryonic epithelial cells. Mutations in this gene are associated with focal segmental glomerulosclerosis 9, and with ventriculomegaly with cystic kidney disease. [provided by RefSeq, Aug 2016]

MANE transcript

NM_173689.7

Inheritance

AR, AD

ClinVar variants

P:63U:385B:293

Top phenotype

Focal segmental glomerulosclerosis 9; Ventriculomegaly with cystic kidney disease

gnomAD constraint

pLI —, LoF o/e 0.65

Max pathogenic AF

—

Genomic locus

chr9:123,356,170-123,380,324

External References & Databases

Ensembl (ENSG00000148204)

Transcript & Mutation Effects

hg38 • Region Span ~24.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ventriculomegaly-cystic kidney diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009063

Submitter: Orphanet

ventriculomegaly-cystic kidney diseaseDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009063

Submitter: G2P

ventriculomegaly-cystic kidney diseaseSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009063

Submitter: Genomics England PanelApp

focal segmental glomerulosclerosis 9DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014539

Submitter: ClinGen

The *CRB2* gene is located on chromosome 9 at q33.3 and encodes the crumbs cell polarity complex component 2 protein which plays a role in many cellular processes in early embryonic development, including: epithelial-to-mesenchymal transition at gastrulation, when mesodermal cells move inside the embryo; apical polarity complex maintenance in the cerebral cortex, in the retina and in photoreceptor polarity; and interacts with nephrin in slit diaphragm. *CRB2* mutation was first reported in relation to familial idiopathic steroid resistant nephrotic syndrome (also known as focal segmental glomerulosclerosis 9; FSGS9) by Ebarasi (2015; PMID: 25557779) and with ventriculomegaly with cystic kidney disease by Slavotinek (2015, PMID: 25557780). Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in the molecular mechanism or inheritance pattern and noted phenotypic overlap. Therefore, the following disease entities have been lumped into one disease entity, FSGS9 (OMIM:616220) and ventriculomegaly with cystic kidney disease (OMIM:219730). The preferred disease name suggested for this grouping of disorders is ‘Glomerulopathy, with or without ventriculomegaly and renal cysts - CRB2’. Many variants have been reported in *CRB2* including mainly null variants, but also missense changes, and the maximum score for genetic evidence was reached (12 pts). The mechanism of pathogenicity is loss of function. This gene-disease association is also supported by expression studies, protein interaction data, and a non-human model organism. In summary *CRB2* is definitively associated with Glomerulopathy, with or without ventriculomegaly and renal cysts - CRB2. This has been demonstrated in both the research and clinical diagnostic setting, and has been upheld over time.

retinitis pigmentosaLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0019200

Submitter: G2P

familial idiopathic steroid-resistant nephrotic syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019006

Submitter: Orphanet

focal segmental glomerulosclerosis 9STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014539

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Focal segmental glomerulosclerosis 9; Ventriculomegaly with cystic kidney diseaseAR

Manifestation: Neurologic; Renal

Intervention: Renal

Rationale: The condition can involve steroid-resistant nephrotic syndrome, and early diagnosis may allow early and more specific management

Refs: 25557779; 25557780

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CRB2 variants in ClinVar

14 Conditions Cataloged

not providedTotal: 602

Inborn genetic diseasesTotal: 265

CRB2-related disorderTotal: 116

not specifiedTotal: 98

Focal segmental glomerulosclerosis 9Total: 65

Ventriculomegaly-cystic kidney diseaseTotal: 40

ObesityTotal: 2

Steroid-resistant nephrotic syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_173689.7. 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			6 clinvar	215 clinvar	4 clinvar	225
missense	3 clinvar	13 clinvar	374 clinvar	74 clinvar		464
nonsense	11 clinvar	6 clinvar				17
start loss			1 clinvar			1
frameshift	13 clinvar	15 clinvar	4 clinvar			32
splice donor/acceptor (+/-2bp)	1 clinvar	1 clinvar				2
Total	28	35	385	289	4	741

Highest pathogenic variant AF is 0.0016079978

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 16 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_173689.7	RefSeq	NP_775960.4	13	MANE Select
ENST00000373631.8	Ensembl	ENSP00000362734.3	13	MANE Select
ENST00000359999.7	Ensembl	ENSP00000353092.3	10	Standard
ENST00000460253.1	Ensembl	ENSP00000435279.1	8	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
crb2a	Danio rerio	Structure: cardiac muscle cell Quality: structure abnormal

Gene / Model

Organism

Observed Phenotype

crb2a

Danio rerio

Structure: cardiac muscle cell

Quality: structure

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Hippo signaling pathway - Homo sapiens (human)

Biological Process

mesoderm formation
somitogenesis
heterophilic cell-cell adhesion via plasma membrane cell adhesion molecules
regulation of gastrulation
positive regulation of epithelial to mesenchymal transition

Molecular Function

calcium ion binding
aspartic-type endopeptidase inhibitor activity
protein-containing complex binding

Cellular Component

plasma membrane
integral component of membrane
apical plasma membrane
protein-containing complex
membrane raft

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000373631
Coding exons: 13
Length: 24155
Individuals with no LoFs: 125666
Homozygous LoFs: 0
Heterozygous LoFs: 81
Defined: 125747
p: 0.000322

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.11	662	747	0.886	0.0000482	7989
Missense (PolyPhen)		67	82.694	0.81022		830
Synonymous	-0.252	353	347	1.02	0.0000250	2811
Loss of Function	2.16	29	44.5	0.651	0.00000237	470

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000063	0.000062	rare
Latino/Admixed American	0.00029	0.00029	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00038	0.00038	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.00036	0.00035	rare
South Asian	0.00063	0.00062	rare
Other	0.00050	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Apical polarity protein that plays a central role during the epithelial-to-mesenchymal transition (EMT) at gastrulation, when newly specified mesodermal cells move inside the embryo. Acts by promoting cell ingression, the process by which cells leave the epithelial epiblast and move inside the embryo to form a new tissue layer. The anisotropic distribution of CRB2 and MYH10/myosin-IIB at cell edges define which cells will ingress: cells with high apical CRB2 are probably extruded from the epiblast by neighboring cells with high levels of apical MYH10/myosin-IIB. Also required for maintenance of the apical polarity complex during development of the cortex. {ECO:0000250|UniProtKB:Q80YA8}.;
Disease: DISEASE: Focal segmental glomerulosclerosis 9 (FSGS9) [MIM:616220]: A renal pathology defined by the presence of segmental sclerosis in glomeruli and resulting in proteinuria, reduced glomerular filtration rate and progressive decline in renal function. Renal insufficiency often progresses to end-stage renal disease, a highly morbid state requiring either dialysis therapy or kidney transplantation. {ECO:0000269|PubMed:25557779}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Ventriculomegaly with cystic kidney disease (VMCKD) [MIM:219730]: A severe autosomal recessive developmental disorder manifesting in utero. It is characterized by cerebral ventriculomegaly, echogenic kidneys, microscopic renal tubular cysts and findings of congenital nephrosis. {ECO:0000269|PubMed:25557780}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.121

Intolerance Scores

LoFtool: 0.103
RVIS EVS: 0.1
RVIS percentile EVS: 61.28

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.807

Gene Damage Prediction

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