rs78984783
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.3528delC(p.Lys1177fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000171 in 1,613,238 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00018 ( 0 hom. )
Consequence
CFTR
NM_000492.4 frameshift
NM_000492.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.180
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-117627579-AC-A is Pathogenic according to our data. Variant chr7-117627579-AC-A is described in ClinVar as [Pathogenic]. Clinvar id is 35868.Status of the report is practice_guideline, 4 stars. Variant chr7-117627579-AC-A is described in Lovd as [Pathogenic]. Variant chr7-117627579-AC-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.3528delC | p.Lys1177fs | frameshift_variant | 22/27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.3528delC | p.Lys1177fs | frameshift_variant | 22/27 | 1 | NM_000492.4 | ENSP00000003084.6 |
Frequencies
GnomAD3 genomes AF: 0.0000920 AC: 14AN: 152174Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000168 AC: 42AN: 250746Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135496
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GnomAD4 exome AF: 0.000179 AC: 262AN: 1461064Hom.: 0 Cov.: 32 AF XY: 0.000184 AC XY: 134AN XY: 726812
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GnomAD4 genome AF: 0.0000920 AC: 14AN: 152174Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7AN XY: 74348
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:22Other:1
Revision: practice guideline
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:11Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 05, 2022 | The c.3528delC pathogenic mutation, located in coding exon 22 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 3528, causing a translational frameshift with a predicted alternate stop codon (p.K1177Sfs*15). This alteration was identified in an individual with cystic fibrosis in conjunction with p.G551D (Adam RJ et al. JCI Insight, 2016 Apr;1:e86183). This alteration is also associated with elevated sweat chloride levels, decreased lung function, and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Of note, this alteration is also known as 3659delC in published literature. In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 08, 2020 | - - |
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 12, 2019 | NM_000492.3(CFTR):c.3528delC(K1177Sfs*15, aka 3659delC) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of this disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.3528delC(K1177Sfs*15, aka 3659delC) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening. - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Dec 08, 2020 | Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. - |
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 05, 2020 | The p.Lys1117SerfsX15 variant in CFTR (c.3528delC, also reported in the past as c.3659delC) is a well-established pathogenic variant in individuals with cystic fibrosis and is often associated with pancreatic insufficiency. It was classified as pathogenic on Mar 17, 2017 by the ClinGen-approved CFTR2 expert panel and is included in the ACMG Technical Standards and Guidelines for CFTR Mutation Testing (ClinVar Variation ID 35868) (Kerem 1990 PMID:2236053, Grody 2001 PMID:11280952, Sosnay 2013 PMID:23974870, Ooi 2012 PMID: 22658665). It has also been identified in 0.028% (36/128698) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1117 and leads to a premature termination codon 15 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of the CFTR gene is an established disease mechanism in autosomal recessive cystic fibrosis and other CFTR-related disorders. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive CFTR-related disorders. ACMG/AMP Criteria applied: PVS1, PM3_Strong, PM2_Supporting. - |
Pathogenic, no assertion criteria provided | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 03, 2015 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 13, 2024 | This sequence change creates a premature translational stop signal (p.Lys1177Serfs*15) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs762828343, gnomAD 0.03%). This premature translational stop signal has been observed in individual(s) with cystic fibrosis (PMID: 15371902, 23974870). This variant is also known as c.3659delC . ClinVar contains an entry for this variant (Variation ID: 35868). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, practice guideline | curation | American College of Medical Genetics and Genomics (ACMG) | Mar 03, 2004 | - - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
not provided Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 13, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Oct 02, 2023 | - - |
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 | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 31, 2023 | The CFTR c.3528del, p.Lys1177SerfsTer15 variant (rs78984783), also known as 3659delC, is reported in the literature in numerous individuals affected with cystic fibrosis and is often associated with pancreatic insufficiency (Kerem 1990, Sosnay 2013, CFTR2 database). The variant is listed in ClinVar (Variation ID: 35868), and observed in the general population at a frequency of 0.016% (44/282148 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based available information, this variant is considered to be pathogenic. References: Link to CFTR2 database: http://cftr2.org/ Kerem B et al. Identification of mutations in regions corresponding to the two putative nucleotide (ATP)-binding folds of the cystic fibrosis gene. Proc Natl Acad Sci U S A. 1990; 87(21):8447-51. PMID: 2236053. 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jun 30, 2023 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
CFTR-related disorder Pathogenic:3
Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Mar 08, 2020 | - - |
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 14, 2024 | The CFTR c.3528delC variant is predicted to result in a frameshift and premature protein termination (p.Lys1177Serfs*15). This variant, also described as 3659delC, has previously been reported to be causative for cystic fibrosis (Kerem et al. 1990. PubMed ID: 2236053; Sosnay et al. 2013. PubMed ID: 23974870; https://cftr2.org/). This variant is reported in 0.028% of alleles in individuals of European (non-Finnish) descent in gnomAD. Frameshift variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 30, 2024 | - - |
Computational scores
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Details are displayed if max score is > 0.2
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