GUCY2C

protein-coding

guanylate cyclase 2C, the group of Transmembrane guanylate cyclases

Gene summary

This gene encodes a transmembrane protein that functions as a receptor for endogenous peptides guanylin and uroguanylin, and the heat-stable E. coli enterotoxin. The encoded protein activates the cystic fibrosis transmembrane conductance regulator. Mutations in this gene are associated with familial diarrhea (autosomal dominant) and meconium ileus (autosomal recessive). [provided by RefSeq, Nov 2016]

Previous symbols:

GUC2C

MANE transcript

NM_004963.4

Inheritance

AD, AR

ClinVar variants

P:26U:536B:181

Top phenotype

Diarrhea 6; Meconium ileus

gnomAD constraint

pLI —, LoF o/e 0.85

Max pathogenic AF

—

Genomic locus

chr12:14,612,632-14,696,599

External References & Databases

Ensembl (ENSG00000070019)

Transcript & Mutation Effects

hg38 • Region Span ~84.0 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

congenital diarrhea 6DEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013825

Submitter: G2P

congenital diarrhea 6SUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0013825

Submitter: Orphanet

intestinal obstruction in the newborn due to guanylate cyclase 2C deficiencySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013843

Submitter: Orphanet

congenital diarrhea 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013825

Submitter: Labcorp Genetics (formerly Invitae)

intestinal obstruction in the newborn due to guanylate cyclase 2C deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013843

Submitter: Labcorp Genetics (formerly Invitae)

intestinal obstruction in the newborn due to guanylate cyclase 2C deficiencyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013843

Submitter: G2P

congenital diarrhea 6LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0013825

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

congenital diarrhea 6STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0013825

Submitter: PanelApp Australia

congenital sodium diarrheaSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0015170

Submitter: Orphanet

intestinal obstruction in the newborn due to guanylate cyclase 2C deficiencySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013843

Submitter: PanelApp Australia

Clinical Genomic Database (CGD)

Diarrhea 6; Meconium ileusAD/AR

Manifestation: Gastrointestinal; Renal

Intervention: Gastrointestinal; Renal

Rationale: In Diarrhea 6, individuals may present in infancy with relatively severe dehydration, metabolic acidosis, and electrolyte disturbances, and preventive measures and early treatment may be beneficial; Awareness of sequelae that may require surgical interventions (eg, small bowel obstruction) may allow prompt recognition and treatment; Individuals may be at increased risk of urolithiasis, and preventive measures and prompt treatment may be beneficial; In Meconium ileus, individuals may present in infancy with relatively severe dehydration, metabolic acidosis, and electrolyte disturbances, and preventive measures and early treatment may be beneficial

Comments: Individuals with Meconium ileus have been described with features of Diarrhea 6 (in terms of chronic diarrhea in infancy)

Refs: 4006357; 22436048; 22436048; 22521417

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to GUCY2C variants in ClinVar

14 Conditions Cataloged

not providedTotal: 855

Inborn genetic diseasesTotal: 148

not specifiedTotal: 72

GUCY2C-related disorderTotal: 35

Congenital diarrhea 6Total: 23

Intestinal obstruction in the newborn due to guanylate cyclase 2C deficiencyTotal: 18

Meconium ileusTotal: 12

GUCY2C-related disordersTotal: 7

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004963.4. 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			10 clinvar	156 clinvar	4 clinvar	170
missense	7 clinvar	7 clinvar	462 clinvar	21 clinvar		497
nonsense		4 clinvar	23 clinvar			27
start loss						0
frameshift	1 clinvar	7 clinvar	22 clinvar			30
splice donor/acceptor (+/-2bp)			19 clinvar			19
Total	8	18	536	177	4	743

Highest pathogenic variant AF is 0.000013111708

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 10 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004963.4	RefSeq	NP_004954.2	27	MANE Select
ENST00000261170.5	Ensembl	ENSP00000261170.3	27	MANE Select
ENST00000867619.1	Ensembl	ENSP00000537678.1	28	Standard
ENST00000867619.2	Ensembl	ENSP00000537678.1	28	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Purine metabolism - Homo sapiens (human)
Disease
Intestinal infectious diseases
Uptake and actions of bacterial toxins
Infectious disease

Biological Process

cGMP biosynthetic process
protein phosphorylation
signal transduction
receptor guanylyl cyclase signaling pathway
digestion

Molecular Function

peptide receptor activity
guanylate cyclase activity
protein kinase activity
protein binding
ATP binding

Cellular Component

endoplasmic reticulum membrane
plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261170
Coding exons: 27
Length: 83944
Individuals with no LoFs: 125583
Homozygous LoFs: 0
Heterozygous LoFs: 165
Defined: 125748
p: 0.000656

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.25	500	585	0.855	0.0000308	7096
Missense (PolyPhen)		159	231.13	0.68793		2778
Synonymous	1.49	185	213	0.870	0.0000116	1964
Loss of Function	1.04	51	59.7	0.854	0.00000322	720

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0012	0.0012	notable
Latino/Admixed American	0.00091	0.00078	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00049	0.00049	rare
Finnish	0.00018	0.00018	rare
European (Non-Finnish)	0.00075	0.00074	rare
South Asian	0.00063	0.00062	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Receptor for the E.coli heat-stable enterotoxin (E.coli enterotoxin markedly stimulates the accumulation of cGMP in mammalian cells expressing GC-C). Also activated by the endogenous peptides guanylin and uroguanylin.;
Disease: DISEASE: Diarrhea 6 (DIAR6) [MIM:614616]: A relatively mild, early-onset chronic diarrhea that may be associated with increased susceptibility to inflammatory bowel disease, small bowel obstruction, and esophagitis. {ECO:0000269|PubMed:22436048}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Meconium ileus (MECIL) [MIM:614665]: A condition characterized by a intestinal obstruction due to inspissated meconium in the distal ileum and cecum, which develops in utero and presents shortly after birth as a failure to pass meconium. Meconium ileus is a known clinical manifestation of cystic fibrosis. {ECO:0000269|PubMed:22521417}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.153

Intolerance Scores

LoFtool: 0.374
RVIS EVS: -1.1
RVIS percentile EVS: 6.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.873

Gene Damage Prediction

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