GeneBe

CFTR

protein-coding

CF transmembrane conductance regulator, the group of ATP binding cassette subfamily C|Chloride channels, ATP-gated CFTR

Gene summary

This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]

Previous symbols:
  • CF
  • ABCC7

MANE transcript

NM_000492.4

Inheritance

AR, AD

ClinVar variants

P:1636U:2267B:1078

Top phenotype

Cystic fibrosis

gnomAD constraint

pLI —, LoF o/e 1.09

Max pathogenic AF

—

Genomic locus

chr7:117,287,120-117,715,971

External References & Databases

Ensembl (ENSG00000001626)NCBI Gene (1080)OMIM (602421)HGNC:1884GenCCUniProt (P13569)AlphaFoldClinVar (CFTR)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~428.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

cystic fibrosisSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0009061

Submitter: Labcorp Genetics (formerly Invitae)

cystic fibrosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009061

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 bilateral absence of vas deferensSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018801

Submitter: Orphanet

cystic fibrosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009061

Submitter: Myriad Women's Health

cystic fibrosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009061

Submitter: ClinGen

*CFTR* was first reported in relation to autosomal recessive cystic fibrosis (CF) in 1989 (Riordan et al., PMID: 2475911). CF is a disease generally characterized by chronic obstructive pulmonary disease, exocrine pancreatic insufficiency, and elevated sodium and chloride concentration in sweat. Infertility is common among male patients (due to congenital bilateral absence of vas deferens) and decreased longevity is common in all patients, although recent therapies have enhanced patient outcomes and increased longevity. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found differences in phenotypic variability. Therefore, this curation is only concerning *CFTR * and cystic fibrosis. The other disease entities associated with *CFTR* including sweat chloride elevation, aquagenic palmoplantar keratoderma (Orphanet:498359), and hereditary pancreatitis (OMIM:167800) are not evaluated in this curation. Eleven variants (missense, in-frame indel, nonsense, and frameshift) that have been reported in 6 probands in 6 publications (PMIDs: 1682496, 1757966, 7477025, 15614862, 18306312, 31187952, 32454915) are included in this curation. Of note, the ∆F508 variant, c.1521_1523del (p.Phe508del), is reported to be present in ~70% of CF cases (Kerem et al., PMID: 2570460). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is known to be LOF. This gene-disease association is also supported by experimental evidence (animal models, in vitro functional assays, and biochemical function) (PMIDs: 7540133, 7545494, 7685652, 10330420, 24727426). Loss of function in *CFTR* causes Cl- channel dysfunction in the apical membrane of epithelial tissues across the body, leading to the disruption of fluid and electrolyte transport, the quantity and composition of epithelial fluids, and healthy organ function (Wang et al., PMID: 24727426). This is supported by altered protein trafficking, processing, and/or function as demonstrated by the ΔF508, c.1679G>C (p.R560T), and c.14C>T (p.P5L) variants as well as a *CFTR*-null mouse model (Ratcliff et al., PMID: 7685652) and a homozygous ΔF508 mouse model (Colledge et al., PMID: 7545494). In summary, *CFTR* is definitively associated with autosomal recessive cystic fibrosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

cystic fibrosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009061

Submitter: Natera

congenital bilateral aplasia of vas deferens from CFTR mutationDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0010178

Submitter: Natera

hereditary chronic pancreatitisLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0008185

Submitter: Labcorp Genetics (formerly Invitae)

cystic fibrosisSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009061

Submitter: Orphanet

Clinical Genomic Database (CGD)

Cystic fibrosisAR

Manifestation: Allergy/Immunology/Infectious; Endocrine; Gastrointestinal; Genitourinary; Pulmonary

Intervention: Allergy/Immunology/Infectious; Endocrine; Gastrointestinal; Pulmonary

Rationale: Early and aggressive multisystem management of pulmonary (with attention to infectious risks), pancreatic, and other manifestations can reduce morbidity and mortality; In the instance of specific variants, targeted therapy (eg, ivacaftor) has been described as beneficial

Refs: 5657013; 2296270; 1870650; 1284639; 1359500; 7678316; 7680769; 7739684; 7529962; 7539210; 9003498; 9395429; 9113931; 9150159; 9550361; 18685558; 9725921; 11134427; 12768409; 15948195; 17018651; 16778595; 17202412; 7413420; 18685558; 21083385; 21184098; 22047557; 22383668; 22942289; 23590265; 23616732; 23616952; 23757359; 23952705; 24004658; 24039402Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CFTR variants in ClinVar

40 Conditions Cataloged
Cystic fibrosisTotal: 5233
CFTR-related disorderTotal: 1700
not providedTotal: 1069
not specifiedTotal: 977
Bronchiectasis with or without elevated sweat chloride 1Total: 614
Congenital bilateral aplasia of vas deferens from CFTR mutationTotal: 482
Hereditary pancreatitisTotal: 420
Cystic fibrosis diagnostic testTotal: 45

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_000492.4. 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.

EffectPLPVUSLBBSum
synonymous
13
clinvar
11
clinvar
58
clinvar
1024
clinvar
8
clinvar
 1114
missense
166
clinvar
300
clinvar
2152
clinvar
44
clinvar
2
clinvar
 2664
nonsense
206
clinvar
118
clinvar
13
clinvar
 337
start loss
5
clinvar
1
clinvar
1
clinvar
 7
frameshift
351
clinvar
255
clinvar
26
clinvar
 632
splice donor/acceptor (+/-2bp)
109
clinvar
101
clinvar
17
clinvar
 227
Total85078622671068104981

Highest pathogenic variant AF is 0.0119312545

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 46 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_000492.4RefSeqNP_000483.327MANE Select
ENST00000003084.11EnsemblENSP00000003084.627MANE Select
ENST00000426809.5EnsemblENSP00000389119.126Standard
ENST00000446805.2EnsemblENSP00000417012.12Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
cftrDanio rerio

Structure: secondary islet

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Tight junction - Homo sapiens (human)
  • Bile secretion - Homo sapiens (human)
  • Gastric acid secretion - Homo sapiens (human)
  • AMPK signaling pathway - Homo sapiens (human)
  • ABC transporters - Homo sapiens (human)

Biological Process

  • cholesterol biosynthetic process
  • vesicle docking involved in exocytosis
  • bicarbonate transport
  • protein deubiquitination
  • cholesterol transport

Molecular Function

  • chloride channel activity
  • intracellularly ATP-gated chloride channel activity
  • protein binding
  • ATP binding
  • bicarbonate transmembrane transporter activity

Cellular Component

  • nucleus
  • cytoplasm
  • lysosomal membrane
  • early endosome
  • endoplasmic reticulum membrane

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000003084
Coding exons
27
Length
250188
Individuals with no LoFs
125053
Homozygous LoFs
0
Heterozygous LoFs
695
Defined
125748
p
0.00277
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-3.149967531.320.00003809674
Missense (PolyPhen)180116.881.54011501
Synonymous0.7742562720.9400.00001422819
Loss of Function-0.7348477.01.090.00000404938

Population LoF Frequency

PopulationCAFp-valueStatus
African0.00350.0035notable
Latino/Admixed American0.00260.0026notable
Ashkenazi Jewish0.0110.011notable
East Asian0.000490.00049rare
Finnish0.00170.0017notable
European (Non-Finnish)0.00270.0027notable
South Asian0.00240.0024notable
Other0.00160.0016notable

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Epithelial ion channel that plays an important role in the regulation of epithelial ion and water transport and fluid homeostasis (PubMed:26823428). Mediates the transport of chloride ions across the cell membrane (PubMed:10792060, PubMed:11524016, PubMed:11707463, PubMed:12519745, PubMed:15010471, PubMed:12588899, PubMed:17036051, PubMed:19398555, PubMed:19621064, PubMed:22178883, PubMed:25330774, PubMed:1712898, PubMed:8910473, PubMed:9804160, PubMed:12529365, PubMed:17182731, PubMed:26846474, PubMed:28087700). Channel activity is coupled to ATP hydrolysis (PubMed:8910473). The ion channel is also permeable to HCO(3-); selectivity depends on the extracellular chloride concentration (PubMed:15010471, PubMed:19019741). Exerts its function also by modulating the activity of other ion channels and transporters (PubMed:12403779, PubMed:22178883, PubMed:22121115, PubMed:27941075). Plays an important role in airway fluid homeostasis (PubMed:16645176, PubMed:19621064, PubMed:26823428). Contributes to the regulation of the pH and the ion content of the airway surface fluid layer and thereby plays an important role in defense against pathogens (PubMed:14668433, PubMed:16645176, PubMed:26823428). Modulates the activity of the epithelial sodium channel (ENaC) complex, in part by regulating the cell surface expression of the ENaC complex (PubMed:17434346, PubMed:27941075, PubMed:17182731). Inhibits the activity of the ENaC channel containing subunits SCNN1A, SCNN1B and SCNN1G (PubMed:17182731). Inhibits the activity of the ENaC channel containing subunits SCNN1D, SCNN1B and SCNN1G, but not of the ENaC channel containing subunits SCNN1A, SCNN1B and SCNN1G (PubMed:27941075). May regulate bicarbonate secretion and salvage in epithelial cells by regulating the transporter SLC4A7 (PubMed:12403779). Can inhibit the chloride channel activity of ANO1 (PubMed:22178883). Plays a role in the chloride and bicarbonate homeostasis during sperm epididymal maturation and capacitation (PubMed:19923167, PubMed:27714810). {ECO:0000269|PubMed:10792060, ECO:0000269|PubMed:11524016, ECO:0000269|PubMed:11707463, ECO:0000269|PubMed:12403779, ECO:0000269|PubMed:12519745, ECO:0000269|PubMed:12529365, ECO:0000269|PubMed:12588899, ECO:0000269|PubMed:14668433, ECO:0000269|PubMed:15010471, ECO:0000269|PubMed:16645176, ECO:0000269|PubMed:17036051, ECO:0000269|PubMed:1712898, ECO:0000269|PubMed:17182731, ECO:0000269|PubMed:19019741, ECO:0000269|PubMed:19398555, ECO:0000269|PubMed:19621064, ECO:0000269|PubMed:22178883, ECO:0000269|PubMed:25330774, ECO:0000269|PubMed:26627831, ECO:0000269|PubMed:26823428, ECO:0000269|PubMed:26846474, ECO:0000269|PubMed:27714810, ECO:0000269|PubMed:27941075, ECO:0000269|PubMed:28087700, ECO:0000269|PubMed:8910473, ECO:0000269|PubMed:9804160, ECO:0000305|PubMed:19923167}.;
Disease
DISEASE: Cystic fibrosis (CF) [MIM:219700]: A common generalized disorder of the exocrine glands which impairs clearance of secretions in a variety of organs. It is characterized by the triad of chronic bronchopulmonary disease (with recurrent respiratory infections), pancreatic insufficiency (which leads to malabsorption and growth retardation) and elevated sweat electrolytes. It is the most common genetic disease in Caucasians, with a prevalence of about 1 in 2'000 live births. Inheritance is autosomal recessive. {ECO:0000269|PubMed:10094564, ECO:0000269|PubMed:11242048, ECO:0000269|PubMed:12167682, ECO:0000269|PubMed:12394343, ECO:0000269|PubMed:12529365, ECO:0000269|PubMed:1284466, ECO:0000269|PubMed:1284468, ECO:0000269|PubMed:1284529, ECO:0000269|PubMed:1284530, ECO:0000269|PubMed:1284548, ECO:0000269|PubMed:1379210, ECO:0000269|PubMed:15528182, ECO:0000269|PubMed:15716351, ECO:0000269|PubMed:16822950, ECO:0000269|PubMed:1695717, ECO:0000269|PubMed:1699669, ECO:0000269|PubMed:17098864, ECO:0000269|PubMed:1710600, ECO:0000269|PubMed:1712898, ECO:0000269|PubMed:17182731, ECO:0000269|PubMed:20008117, ECO:0000269|PubMed:20150177, ECO:0000269|PubMed:20691141, ECO:0000269|PubMed:2236053, ECO:0000269|PubMed:25330774, ECO:0000269|PubMed:26846474, ECO:0000269|PubMed:28001373, ECO:0000269|PubMed:28087700, ECO:0000269|PubMed:7504969, ECO:0000269|PubMed:7505694, ECO:0000269|PubMed:7513296, ECO:0000269|PubMed:7517264, ECO:0000269|PubMed:7520022, ECO:0000269|PubMed:7522211, ECO:0000269|PubMed:7524909, ECO:0000269|PubMed:7524913, ECO:0000269|PubMed:7525450, ECO:0000269|PubMed:7537150, ECO:0000269|PubMed:7541273, ECO:0000269|PubMed:7541510, ECO:0000269|PubMed:7543567, ECO:0000269|PubMed:7544319, ECO:0000269|PubMed:7581407, ECO:0000269|PubMed:7606851, ECO:0000269|PubMed:7680525, ECO:0000269|PubMed:7683628, ECO:0000269|PubMed:7683954, ECO:0000269|PubMed:8081395, ECO:0000269|PubMed:8406518, ECO:0000269|PubMed:8522333, ECO:0000269|PubMed:8723693, ECO:0000269|PubMed:8723695, ECO:0000269|PubMed:8800923, ECO:0000269|PubMed:8829633, ECO:0000269|PubMed:8910473, ECO:0000269|PubMed:8956039, ECO:0000269|PubMed:9101301, ECO:0000269|PubMed:9222768, ECO:0000269|PubMed:9375855, ECO:0000269|PubMed:9401006, ECO:0000269|PubMed:9443874, ECO:0000269|PubMed:9452048, ECO:0000269|PubMed:9452054, ECO:0000269|PubMed:9452073, ECO:0000269|PubMed:9482579, ECO:0000269|PubMed:9521595, ECO:0000269|PubMed:9554753, ECO:0000269|PubMed:9736778, ECO:0000269|PubMed:9804160, ECO:0000269|PubMed:9921909}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Congenital bilateral absence of the vas deferens (CBAVD) [MIM:277180]: Important cause of sterility in men and could represent an incomplete form of cystic fibrosis, as the majority of men suffering from cystic fibrosis lack the vas deferens. {ECO:0000269|PubMed:10651488, ECO:0000269|PubMed:17329263, ECO:0000269|PubMed:7529962, ECO:0000269|PubMed:7539342, ECO:0000269|PubMed:9067761, ECO:0000269|PubMed:9736778, ECO:0000269|Ref.113}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.877

Intolerance Scores

LoFtool
0.0235
RVIS EVS
-0.51
RVIS percentile EVS
21.73

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.695

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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