chr7-117509035-GA-G
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.168del(p.Glu56AspfsTer35) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,442,320 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. E56E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000492.4 frameshift, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.168del | p.Glu56AspfsTer35 | frameshift_variant, splice_region_variant | 3/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.168del | p.Glu56AspfsTer35 | frameshift_variant, splice_region_variant | 3/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000277 AC: 4AN: 1442320Hom.: 0 Cov.: 28 AF XY: 0.00000417 AC XY: 3AN XY: 719018
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:4Other:1
Pathogenic, reviewed by expert panel | research | CFTR2 | Sep 24, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Oct 04, 2019 | This frameshift variant results in a premature stop codon in exon 3 likely leading to nonsense-mediated decay and lack of protein production. This CFTR variant is absent from large population datasets and is reported in ClinVar, however, no classification is provided. CFTR c.168delA has been identified in multiple cystic fibrosis patients who also carry a second pathogenic variant. We consider this variant to be pathogenic. - |
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 27, 2022 | Variant summary: CFTR c.168delA (p.Glu56AspfsX35) 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. The variant was absent in 250694 control chromosomes (gnomAD). c.168delA has been reported in the literature in several individuals affected with Cystic Fibrosis (e.g. Claustres_1993, Schwarz_1995, Claustres_2000, des Georges_2004). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters, including one expert panel (CFTR2), have assessed the variant since 2014: all five classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 24, 2019 | The variant results in a shift of the reading frame, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data. - |
CFTR-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at