rs193922505
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The ENST00000003084.11(CFTR):c.1692del(p.Asp565MetfsTer7) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000187 in 1,602,588 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 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
CFTR
ENST00000003084.11 frameshift
ENST00000003084.11 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 8.64
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 7-117590362-CA-C is Pathogenic according to our data. Variant chr7-117590362-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 35831.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117590362-CA-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.1692del | p.Asp565MetfsTer7 | frameshift_variant | 13/27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.1692del | p.Asp565MetfsTer7 | frameshift_variant | 13/27 | 1 | NM_000492.4 | ENSP00000003084 | P2 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151874Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250388Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135434
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GnomAD4 exome AF: 6.89e-7 AC: 1AN: 1450714Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1AN XY: 721514
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151874Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2AN XY: 74168
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:9
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2023 | The c.1692delA pathogenic mutation, located in coding exon 13 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 1692, causing a translational frameshift with a predicted alternate stop codon (p.D565Mfs*7). 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 | Labcorp Genetics (formerly Invitae), Labcorp | Apr 13, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 35831). This premature translational stop signal has been observed in individual(s) with a positive newborn screening result for CFTR-related disease (PMID: 26574590). This variant is present in population databases (rs753782103, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Asp565Metfs*7) 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). - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 31, 2023 | Variant summary: CFTR c.1692delA (p.Asp565MetfsX7) results in a premature termination codon, predicted to cause absence of the protein due to nonsense mediated decay, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 1.2e-05 in 250388 control chromosomes (gnomAD). c.1692delA has been reported in the literature in individuals affected with Cystic Fibrosis (Kharrazi_2015, Raraigh_2022). These data indicate that the variant is likely associated with disease. The following publications have been ascertained in the context of this evaluation (PMID: 26574590, 34782259). Seven submitters, including an expert panel, have provided clinical-significance assessments for this variant to ClinVar after 2014, and classified it as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 20, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Apr 02, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 26574590) - |
Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Nov 25, 2019 | PVS1, PM2, PP5 - |
Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | - | - - |
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 31, 2022 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at