PTCH2

protein-coding

patched 2

Gene summary

This gene encodes a transmembrane receptor of the patched gene family. The encoded protein may function as a tumor suppressor in the hedgehog signaling pathway. Alterations in this gene have been associated with nevoid basal cell carcinoma syndrome, basal cell carcinoma, medulloblastoma, and susceptibility to congenital macrostomia. Alternatively spliced transcript variants have been described.[provided by RefSeq, Oct 2009]

MANE transcript

NM_003738.5

Inheritance

ClinVar variants

P:2U:635B:311

Top phenotype

Basal cell nevus syndrome

gnomAD constraint

pLI —, LoF o/e 0.64

Max pathogenic AF

—

Genomic locus

chr1:44,819,154-44,843,253

External References & Databases

Ensembl (ENSG00000117425)

Transcript & Mutation Effects

hg38 • Region Span ~24.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

commissural facial cleftSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013300

Submitter: Orphanet

nevoid basal cell carcinoma syndromeMODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0007187

Submitter: Genomics England PanelApp

nevoid basal cell carcinoma syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007187

Submitter: Orphanet

nevoid basal cell carcinoma syndromeLIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0007187

Submitter: Labcorp Genetics (formerly Invitae)

nevoid basal cell carcinoma syndromeLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007187

Submitter: ClinGen

There is one large family with a specific missense mutation (that is otherwise very rare in gnomAD) with a LOD score 2.41 and for which there is extensive functional studies with a Gorlin-like phenotype. The other report is a frameshift variant in a Japanese individual. The Ptch2 mouse knockout model showed related but milder phenotype with no tumors. The evidence that variants in PTCH2 cause a Gorlin-like phenotype (odontogenic cysts, etc) with milder phenotype and lower penetrance than the PTCH1-associated genotype is limited.

basal cell nevus syndrome 1LIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0958174

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Basal cell nevus syndromeAD

Manifestation: Dermatologic; Musculoskeletal; Oncologic

Intervention: Oncologic

Rationale: Individuals are at risk for a number of types of malignancies, including basal cell carcinomas and medulloblastoma , as well as (rare) malignant rare keratocysttransformation, and awareness and surveillance may allow early diagnosis and treatment (including with molecular therapies that target the Hedgehog signaling pathway), potentially reducing morbidity and mortality; Avoidance of agents such as radiation therapy is indicated

Refs: 18285427; 22670903; 22670904; 23479190

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to PTCH2 variants in ClinVar

15 Conditions Cataloged

Gorlin syndromeTotal: 989

not specifiedTotal: 224

not providedTotal: 99

PTCH2-related disorderTotal: 87

Basal cell carcinoma, susceptibility to, 1Total: 87

MedulloblastomaTotal: 65

Basal cell nevus syndrome 1Total: 38

Breast carcinomaTotal: 2

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003738.5. 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	259 clinvar	11 clinvar	276
missense			554 clinvar	38 clinvar	3 clinvar	595
nonsense			14 clinvar			14
start loss						0
frameshift		2 clinvar	40 clinvar			42
splice donor/acceptor (+/-2bp)			21 clinvar			21
Total	0	2	635	297	14	948

Highest pathogenic variant AF is 0.0000034204406

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 9 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003738.5	RefSeq	NP_003729.3	22	MANE Select
ENST00000372192.4	Ensembl	ENSP00000361266.3	22	MANE Select
NM_001166292.2	RefSeq	NP_001159764.1	23	Standard
ENST00000438067.5	Ensembl	ENSP00000413169.1	5	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
ptch2	Danio rerio	Structure: retinal ganglion cell Quality: mislocalised abnormal

Gene / Model

Organism

Observed Phenotype

ptch2

Danio rerio

Structure: retinal ganglion cell

Quality: mislocalised

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Basal cell carcinoma - Homo sapiens (human)
Pathways in cancer - Homo sapiens (human)
Hedgehog signaling pathway - Homo sapiens (human)
HH-Core
Hedgehog ,on, state

Biological Process

cell fate determination
smoothened signaling pathway
epidermal cell fate specification
hair cycle
skin development

Molecular Function

smoothened binding
hedgehog receptor activity
hedgehog family protein binding

Cellular Component

plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000372192
Coding exons: 22
Length: 23220
Individuals with no LoFs: 125478
Homozygous LoFs: 1
Heterozygous LoFs: 269
Defined: 125748
p: 0.00107

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	0.785	638	696	0.916	0.0000445	7665
Missense (PolyPhen)		166	195.86	0.84756		2196
Synonymous	0.0356	304	305	0.997	0.0000198	2642
Loss of Function	2.43	33	51.9	0.635	0.00000238	561

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00096	0.00095	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.0038	0.0038	notable
Finnish	0.00023	0.00023	rare
European (Non-Finnish)	0.0011	0.0011	notable
South Asian	0.00065	0.00065	rare
Other	0.00099	0.00098	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May have a role in epidermal development. May act as a receptor for Sonic hedgehog (SHH).;
Disease: DISEASE: Medulloblastoma (MDB) [MIM:155255]: Malignant, invasive embryonal tumor of the cerebellum with a preferential manifestation in children. {ECO:0000269|PubMed:9931336}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Basal cell carcinoma (BCC) [MIM:605462]: A common malignant skin neoplasm that typically appears on hair-bearing skin, most commonly on sun-exposed areas. BCC is slow growing and rarely metastasizes, but has potentialities for local invasion and destruction. It usually develops as a flat, firm, pale area that is small, raised, pink or red, translucent, shiny, and waxy, and the area may bleed following minor injury. Tumor size can vary from a few millimeters to several centimeters in diameter. {ECO:0000269|PubMed:9931336}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.198

Intolerance Scores

LoFtool: 0.0291
RVIS EVS: -1.52
RVIS percentile EVS: 3.47

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.961

Gene Damage Prediction

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