GPR68

protein-coding

G protein-coupled receptor 68, the group of G protein-coupled receptors, Class A orphans

Gene summary

The protein encoded by this gene is a G protein-coupled receptor for sphingosylphosphorylcholine. The encoded protein is a proton-sensing receptor, inactive at pH 7.8 but active at pH 6.8. Mutations in this gene are a cause of amelogenesis imperfecta. [provided by RefSeq, Feb 2017]

MANE transcript

NM_001177676.2

Inheritance

ClinVar variants

P:3U:58B:13

Top phenotype

Amelogenesis imperfecta, hypomaturation type, IIA6

gnomAD constraint

pLI —, LoF o/e 0.69

Max pathogenic AF

—

Genomic locus

chr14:91,232,532-91,253,925

External References & Databases

Ensembl (ENSG00000119714)

Transcript & Mutation Effects

hg38 • Region Span ~21.4 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

amelogenesis imperfecta, hypomaturation type, IIa6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014971

Submitter: Labcorp Genetics (formerly Invitae)

amelogenesis imperfecta, hypomaturation type, IIa6LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0014971

Submitter: Ambry Genetics

amelogenesis imperfecta, hypomaturation type, IIa6STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014971

Submitter: PanelApp Australia

amelogenesis imperfecta type 2SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015048

Submitter: Orphanet

Clinical Genomic Database (CGD)

Amelogenesis imperfecta, hypomaturation type, IIA6AR

Manifestation: Dental

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: 27693231

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GPR68 variants in ClinVar

5 Conditions Cataloged

not specifiedTotal: 58

GPR68-related disorderTotal: 9

Amelogenesis imperfecta, hypomaturation type, IIa6Total: 5

not providedTotal: 4

Amelogenesis imperfectaTotal: 4

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001177676.2. 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				9 clinvar	1 clinvar	10
missense	1 clinvar		56 clinvar	3 clinvar		60
nonsense			1 clinvar			1
start loss						0
frameshift	2 clinvar		1 clinvar			3
splice donor/acceptor (+/-2bp)						0
Total	3	0	58	12	1	74

Highest pathogenic variant AF is 0.000001387028

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 27 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_001177676.2	RefSeq	NP_001171147.1	1	MANE Select
ENST00000650645.1	Ensembl	ENSP00000498702.1	1	MANE Select
NM_001348437.1	RefSeq	NP_001335366.1	1	Standard
NM_003485.3	RefSeq	NP_003476.3	1	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Osteoclast Signaling
GPCRs, Class A Rhodopsin-like
Signaling by GPCR
Signal Transduction
Class A/1 (Rhodopsin-like receptors)

Biological Process

inflammatory response
G protein-coupled receptor signaling pathway
positive regulation of insulin secretion involved in cellular response to glucose stimulus
negative regulation of monocyte differentiation
cellular response to pH

Molecular Function

G protein-coupled receptor activity

Cellular Component

plasma membrane
integral component of plasma membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000531499
Coding exons: 1
Length: 21394
Individuals with no LoFs: 125700
Homozygous LoFs: 0
Heterozygous LoFs: 16
Defined: 125716
p: 0.0000636

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.19	173	223	0.775	0.0000152	2317
Missense (PolyPhen)		40	67.9	0.5891		709
Synonymous	-0.262	117	113	1.03	0.00000890	757
Loss of Function	0.832	6	8.64	0.694	3.71e-7	87

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00013	0.00012	rare
Latino/Admixed American	0.000087	0.000087	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0	0.0	absent
Finnish	0	0.0	absent
European (Non-Finnish)	0.000089	0.000088	rare
South Asian	0.000036	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Proton-sensing receptor involved in pH homeostasis. May represents an osteoblastic pH sensor regulating cell-mediated responses to acidosis in bone. Mediates its action by association with G proteins that stimulates inositol phosphate (IP) production or Ca(2+) mobilization. The receptor is almost silent at pH 7.8 but fully activated at pH 6.8. Function also as a metastasis suppressor gene in prostate cancer (By similarity). {ECO:0000250, ECO:0000269|PubMed:12955148}.;

Recessive Scores

pRec: 0.120

Intolerance Scores

LoFtool: 0.461
RVIS EVS: -0.6
RVIS percentile EVS: 17.91

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Indispensability pred.: E
Indispensability score: 0.630

Gene Damage Prediction

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