CELSR1

protein-coding

cadherin EGF LAG seven-pass G-type receptor 1, the group of Adhesion G protein-coupled receptors, subfamily C|CELSR cadherins

Gene summary

The protein encoded by this gene is a member of the flamingo subfamily, part of the cadherin superfamily. The flamingo subfamily consists of nonclassic-type cadherins; a subpopulation that does not interact with catenins. The flamingo cadherins are located at the plasma membrane and have nine cadherin domains, seven epidermal growth factor-like repeats and two laminin A G-type repeats in their ectodomain. They also have seven transmembrane domains, a characteristic unique to this subfamily. It is postulated that these proteins are receptors involved in contact-mediated communication, with cadherin domains acting as homophilic binding regions and the EGF-like domains involved in cell adhesion and receptor-ligand interactions. This particular member is a developmentally regulated, neural-specific gene which plays an unspecified role in early embryogenesis. [provided by RefSeq, Jul 2008]

MANE transcript

NM_001378328.1

Inheritance

AD, AR

ClinVar variants

P:18U:688B:237

Top phenotype

Lymphatic malformation 9

gnomAD constraint

pLI —, LoF o/e 0.17

Max pathogenic AF

—

Genomic locus

chr22:46,360,834-46,537,620

External References & Databases

Ensembl (ENSG00000075275)

Transcript & Mutation Effects

hg38 • Region Span ~176.8 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

epilepsyLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0005027

Submitter: Ambry Genetics

neural tube defects, susceptibility toMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0020705

Submitter: Illumina

hydrops fetalisLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0015193

Submitter: G2P

lymphatic malformation 9STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0030270

Submitter: Labcorp Genetics (formerly Invitae)

genetic developmental and epileptic encephalopathyLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0100062

Submitter: Ambry Genetics

neural tube defects, susceptibility toLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0020705

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Lymphatic malformation 9AD

Manifestation: Cardiovascular

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: 26855770; 31215153; 31403174

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CELSR1 variants in ClinVar

20 Conditions Cataloged

not specifiedTotal: 631

not providedTotal: 247

CELSR1-related disorderTotal: 113

Lymphatic malformation 9Total: 63

Lymphatic malformationTotal: 5

Walker-Warburg congenital muscular dystrophyTotal: 2

Mild NDDTotal: 2

Yellow nail syndromeTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001378328.1. 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			11 clinvar	111 clinvar	34 clinvar	156
missense		5 clinvar	644 clinvar	72 clinvar	18 clinvar	739
nonsense	1 clinvar	2 clinvar	11 clinvar			14
start loss						0
frameshift	2 clinvar	3 clinvar	11 clinvar	2 clinvar		18
splice donor/acceptor (+/-2bp)	3 clinvar	2 clinvar	11 clinvar			16
Total	6	12	688	185	52	943

Highest pathogenic variant AF is 0.00021116911

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001378328.1	RefSeq	NP_001365257.1	35	MANE Select
ENST00000674500.2	Ensembl	ENSP00000501367.2	35	MANE Select
NM_014246.4	RefSeq	NP_055061.1	35	Standard
ENST00000262738.10	Ensembl	ENSP00000262738.3	35	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

GPCRs, Other

Biological Process

establishment of planar polarity
neuron migration
neural tube closure
hair follicle development
homophilic cell adhesion via plasma membrane adhesion molecules

Molecular Function

transmembrane signaling receptor activity
G protein-coupled receptor activity
calcium ion binding
protein dimerization activity

Cellular Component

nucleoplasm
plasma membrane
integral component of plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000262738
Coding exons: 35
Length: 176337
Individuals with no LoFs: 121369
Homozygous LoFs: 365
Heterozygous LoFs: 4014
Defined: 125748
p: 0.0176

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.20	1731	1.88e+3	0.922	0.000136	19376
Missense (PolyPhen)		700	907.13	0.77166		8887
Synonymous	-3.54	1003	870	1.15	0.0000735	6342
Loss of Function	7.97	18	107	0.168	0.00000558	1149

Population LoF Frequency

Population	CAF	p-value	Status
African	0.21	0.21	notable
Latino/Admixed American	0.014	0.012	notable
Ashkenazi Jewish	0.0044	0.0043	notable
East Asian	0.00033	0.00033	rare
Finnish	0.0041	0.0023	notable
European (Non-Finnish)	0.010	0.0059	notable
South Asian	0.0036	0.0019	notable
Other	0.012	0.010	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor that may have an important role in cell/cell signaling during nervous system formation.;
Disease: DISEASE: Neural tube defects (NTD) [MIM:182940]: Congenital malformations of the central nervous system and adjacent structures related to defective neural tube closure during the first trimester of pregnancy. Failure of neural tube closure can occur at any level of the embryonic axis. Common NTD forms include anencephaly, myelomeningocele and spina bifida, which result from the failure of fusion in the cranial and spinal region of the neural tube. NTDs have a multifactorial etiology encompassing both genetic and environmental components. {ECO:0000269|PubMed:22095531}. Note=The disease may be caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.148

Intolerance Scores

LoFtool: 0.157
RVIS EVS: -2.82
RVIS percentile EVS: 0.63

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.804

Gene Damage Prediction

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