rs397508451
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.2896del(p.Thr966ArgfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,570 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Synonymous variant affecting the same amino acid position (i.e. T966T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000492.4 frameshift
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.2896del | p.Thr966ArgfsTer2 | frameshift_variant | 17/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.2896del | p.Thr966ArgfsTer2 | frameshift_variant | 17/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461570Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727082
GnomAD4 genome ? Cov.: 32
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:4
Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 19, 2022 | Variant summary: CFTR c.2896delA (p.Thr966ArgfsX2) 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 251282 control chromosomes. The variant, c.2896delA (aka. 3028delA) has been reported in the literature in multiple compound heterozygous individuals affected with Cystic Fibrosis (e.g. Ooi_2015, McCague_2019, Sasaki_2020). 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. Four submitters, including an expert panel (CFTR2), have provided clinical-significance assessments for this variant in ClinVar after 2014, and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 27, 2016 | The c.2896delA pathogenic mutation (also known as c.3028delA), located in coding exon 17 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 2896, causing a translational frameshift with a predicted alternate stop codon (p.T966Rfs*2).Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 13, 2023 | This sequence change creates a premature translational stop signal (p.Thr966Argfs*2) 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 not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CFTR-related conditions. ClinVar contains an entry for this variant (Variation ID: 53587). For these reasons, this variant has been classified as Pathogenic. - |
CFTR-related disorder Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 19, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at