7-117652877-C-G
Variant names:
Variant summary
Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM5PP3PP5_Very_Strong
The NM_000492.4(CFTR):c.3909C>G(p.Asn1303Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000158 in 1,598,060 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N1303I) has been classified as Pathogenic.
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00016 ( 0 hom. )
Consequence
CFTR
NM_000492.4 missense
NM_000492.4 missense
Scores
10
7
2
Clinical Significance
Conservation
PhyloP100: 0.670
Genes affected
CFTR (HGNC:1884): (CF transmembrane conductance regulator) 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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 15 ACMG points.
PM1
In a helix (size 4) in uniprot entity CFTR_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000492.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr7-117652876-A-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.778
PP5
Variant 7-117652877-C-G is Pathogenic according to our data. Variant chr7-117652877-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 7136.Status of the report is practice_guideline, 4 stars. Variant chr7-117652877-C-G is described in Lovd as [Pathogenic]. Variant chr7-117652877-C-G is described in Lovd as [Pathogenic]. Variant chr7-117652877-C-G is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.3909C>G | p.Asn1303Lys | missense_variant | Exon 24 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.000158 AC: 24AN: 152068Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000144 AC: 36AN: 249546Hom.: 0 AF XY: 0.000171 AC XY: 23AN XY: 134794
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GnomAD4 exome AF: 0.000158 AC: 228AN: 1445874Hom.: 0 Cov.: 27 AF XY: 0.000179 AC XY: 129AN XY: 720082
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GnomAD4 genome 0.000158 AC: 24AN: 152186Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74420
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:41Uncertain:1Other:2
Revision: practice guideline
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:19Uncertain:1Other:2
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Sep 25, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 22, 2025 | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 1303 of the CFTR protein (p.Asn1303Lys). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with CFTR-related disorders, including cystic fibrosis, congenital bilateral absence of the vas deferens, and chronic pancreatitis (PMID: 1380943, 12767731, 15371902, 21520337, 22658665, 23951356, 23974870). ClinVar contains an entry for this variant (Variation ID: 7136). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt CFTR protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CFTR function (PMID: 23891399, 23974870, 25799511). For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 01, 1992 | - - |
| Pathogenic, practice guideline | curation | American College of Medical Genetics and Genomics (ACMG) | Mar 03, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Human Genetics Bochum, Ruhr University Bochum | Sep 23, 2022 | ACMG criteria used to clasify this variant: PS3, PS4, PP3, PP1 - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Jul 26, 2023 | This variant was classified based on the report of 1 patient with a clinically confirmed diagnosis of cystic fibrosis in the context of re-classifying variants in the German Cystic Fibrosis Registry (Muko e.V.). Patients have not been seen personally, but only reports were evaluated. Criteria applied: PS3, PM2_SUP, PM3_VSTR, PM5_STR, PP3, PP4 - |
| Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Apr 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 03, 2016 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre | Apr 04, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
| Pathogenic, no assertion criteria provided | research | Genomics And Bioinformatics Analysis Resource, Columbia University | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 18, 2022 | The p.N1303K pathogenic mutation (also known as c.3909C>G), located in coding exon 24 of the CFTR gene, results from a C to G substitution at nucleotide position 3909. The asparagine at codon 1303 is replaced by lysine, an amino acid with similar properties. In one study, this mutation was identified in 216 cystic fibrosis alleles, including 10 homozygous individuals with elevated sweat chloride levels and decreased lung function. Of the 6 homozygous individuals with reported pancreatic status, all were pancreatic insufficient (Osborne L et al. Hum. Genet., 1992 Aug;89:653-8). In vitro functional studies determined that this mutation prevents the maturation, trafficking, and subsequent activity of the CFTR protein (Gregory RJ et al. Mol. Cell. Biol., 1991 Aug;11:3886-93). This pathogenic mutation is associated with elevated sweat chloride levels, decreased lung function, and pancreatic insufficiency; in vitro functional studies showed this mutation results in significantly reduced chloride conductance (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Sep 01, 2017 | This mutation has been previously reported as disease-causing and was found once in our laboratory in a homozygous state in a 13-year-old male with a clinical diagnosis of cystic fibrosis. Heterozygotes are expected to be asymptomatic carriers. - |
| not provided, no classification provided | phenotyping only | GenomeConnect, ClinGen | - | Variant interpretted as pathogenic and reported on 03/20/2016 by GTR ID 500068. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Courtagen Diagnostics Laboratory, Courtagen Life Sciences | Aug 29, 2014 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 05, 2017 | The CFTR c.3909C>G (p.Asn1303Lys) missense variant is a well-known, widely reported pathogenic variant that accounts for approximately 1.3% of disease alleles, and is often associated with a classic cystic fibrosis (CF) phenotype (Ong et al. 2001). The Cystic Fibrosis Mutation Database (http://www.genet.sickkids.on.ca/cftr/Home.html) indicates that the p.Asn1303Lys variant is the fourth most common CFTR variant worldwide, and the Clinical and Functional Translation of CFTR (CFTR2) database (http://cftr2.org) reports the p.Asn1303Lys variant in over 2100 patients, noting that it is a cystic fibrosis-causing variant. Across a selection of the available literature, the p.Asn1303Lys variant has also been reported in five patients with congenital bilateral absence of the vas deferens (CBAVD), including three compound heterozygotes and two heterozygotes in whom a second variant was not identified (Steiner et al. 2011; Tomaiuolo et al. 2011), and in four patients with chronic pancreatitis, including three compound heterozygotes and one heterozygote (Steiner et al. 2011; Hamoir et al. 2013). The p.Asn1303Lys variant is reported at a frequency of 0.00035 in the European American population of the Exome Sequencing Project. Based on the collective evidence, the p.Asn1303Lys variant is classified as pathogenic for CFTR-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
| Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Undiagnosed Diseases Network, NIH | Oct 10, 2018 | - - |
| Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
| Pathogenic, criteria provided, single submitter | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2024 | PS3,PM3(strong),PP3,PM2,PM5 - |
not provided Pathogenic:14
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Feb 22, 2023 | The frequency of this variant in the general population, 0.00018 (23/128054 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in the homozygous state and with other CF variants in trans to be particularly associated with a pancreatic insufficient phenotype, however, variable lung function phenotypes from unusually mild to severe have been observed (PMID: 1380943 (1992), 23974870 (2013), and 26208274 (2015)). Functional analysis has described this variant as Class II causing defective protein processing, protein degradation, insignificant levels of mature CFTR, and conductance (PMID: 1712898 (1991), 23891399 (2014), 25799511 (2015), 26823392 (2016)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 22, 2022 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics and Genomics, Karolinska University Hospital | May 10, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 15, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 26, 2023 | The CFTR c.3909C>G; p.Asn1303Lys variant (rs80034486), is reported in the literature in multiple individuals diagnosed with cystic fibrosis, often associated with pancreatic insufficiency (Osborne 1991, Osborne 1992, Ooi 2012, Sosnay 2013, CFTR2 database). This variant is reported in ClinVar (Variation ID: 7136), and is found in the general population with an overall allele frequency of 0.014% (34/244424 alleles) in the Genome Aggregation Database. The asparagine at codon 1303 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.83). Functional characterization of the variant protein indicates a defect in CFTR processing, resulting in a severe reduction in chloride transport activity (Sosnay 2013, Van Goor 2014). Based on available information, this variant is considered to be pathogenic. References: CFTR2 database: http://cftr2.org Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 11(5):355-62. PMID: 22658665 Osborne L et al. A mutation in the second nucleotide binding fold of the cystic fibrosis gene. Am J Hum Genet. 1991 48(3):608-12. PMID: 1998343 Osborne L et al. Incidence and expression of the N1303K mutation of the cystic fibrosis (CFTR) gene. Hum Genet. 1992 89(6):653-8. PMID: 1380943 Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 45(10):1160-7. PMID: 23974870 Van Goor F et al. Effect of ivacaftor on CFTR forms with missense mutations associated with defects in protein processing or function. J Cyst Fibros. 2014 13(1):29-36. PMID: 23891399 - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 11, 2015 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2019 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 31, 2018 | The N1303K variant in the CFTR gene has been reported previously as a CF-causing variant in patients with abnormal sweat chloride levels, pancreatic insufficiency, and mild to moderate lung disease (Sosnay et al., 2013; Osborne et al, 1991). The N1303K variant was not observed at any significant frequency in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The N1303K variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position within the ABC transporter 2 domain that is conserved across species. Cell lines expressing the N1303K CFTR variant show loss of baseline chloride transport compared to those expressing wild type protein (Van Goor et al., 2014). A missense variant at the same residue, N1303H, was reported in a patient with severe pulmonary disease and pancreatic insufficiency (Claustres et al., 1992). We interpret N1303K as a pathogenic variant. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Aug 19, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2022 | - - |
CFTR-related disorder Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Sep 25, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 21, 2024 | The CFTR c.3909C>G variant is predicted to result in the amino acid substitution p.Asn1303Lys. This variant has been reported to be causative for cystic fibrosis (Sosnay et al. 2013. PubMed ID: 23974870; Masson et al. 2013. PubMed ID: 23951356; Osborne et al. 1991. PubMed ID: 1998343; Watson et al. 2004. PubMed ID: 15371902). This variant is reported in 0.058% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. This variant is interpreted as pathogenic. - |
Spermatogenic failure, Y-linked, 2 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University Hospital Muenster | Jun 07, 2018 | ACMG categories: PS3,PS4,PP3,PP5 - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Hereditary pancreatitis Pathogenic:1
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | May 25, 2021 | - - |
Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 06, 2024 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 29, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.
REVEL
Pathogenic
Sift
Pathogenic
D;D;.
Sift4G
Uncertain
D;D;.
Polyphen
D;.;.
Vest4
MutPred
Gain of ubiquitination at N1303 (P = 0.03);.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at