rs397508778
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.658C>T(p.Gln220Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000123 in 1,461,828 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 (★★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
CFTR
NM_000492.4 stop_gained
NM_000492.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 3.91
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 7-117535326-C-T is Pathogenic according to our data. Variant chr7-117535326-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 54036.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117535326-C-T is described in Lovd as [Pathogenic]. Variant chr7-117535326-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.658C>T | p.Gln220Ter | stop_gained | 6/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.658C>T | p.Gln220Ter | stop_gained | 6/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251438Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135886
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461828Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727216
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:13
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:9
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 14, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 54036). This premature translational stop signal has been observed in individual(s) with clinical features of cystic fibrosis (PMID: 7515303, 16778407). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is present in population databases (rs397508778, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Gln220*) 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 | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PVS1, PM2_SUP, PM3_VSTR, PP4 - |
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jan 02, 2014 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Jul 26, 2023 | Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 17, 2020 | The p.Q220* pathogenic mutation (also known as c.658C>T), located in coding exon 6 of the CFTR gene, results from a C to T substitution at nucleotide position 658. This changes the amino acid from a glutamine to a stop codon within coding exon 6. This mutation was described in trans with a second pathogenic mutation in an individual presenting with respiratory symptoms, bronchiectasis, and elevated sweat chloride levels (Koh WJ et al. J Korean Med Sci. 2006;21(3):563-6). In addition to pulmonary symptoms and elevated sweat chloride levels, this mutation is also associated with pancreatic insufficiency (Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). 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 | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 28, 2019 | Variant summary: CFTR c.658C>T (p.Gln220X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (c.803delA, p.Asn268fsX17; c.850dupA, p.Met284fsX3; c.948delT, p.Phe316LeufsX12). The variant allele was found at a frequency of 4e-06 in 251438 control chromosomes (gnomAD). The variant, c.658C>T, has been reported in the literature in multiple individuals affected with Cystic Fibrosis (Koh_2006, Tomaiuolo_2010, Ooi_2012, Sosonay_2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One publication, Sosnay_2013, reports that spliced RNA product is less than 10% of WT level predicted by NMD (nonsense mediated decay). Three ClinVar submissions including one expert panel (CFTR2) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified 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 | - | - - |
CFTR-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
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 | Oct 31, 2018 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 22, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
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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