rs200955612
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000492.4(CFTR):c.4097T>A(p.Ile1366Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,736 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 (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1366T) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.4097T>A | p.Ile1366Asn | missense_variant | 25/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.4097T>A | p.Ile1366Asn | missense_variant | 25/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251286Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135796
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461736Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2AN XY: 727188
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Cystic fibrosis Pathogenic:3Uncertain:1
Pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | This variant was identified in 2 unrelated patients 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: PM2_SUP, PM3_STR, PM5_STR, PP3 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 18, 2023 | Variant summary: CFTR c.4097T>A (p.Ile1366Asn) results in a non-conservative amino acid change located in the ATP-binding domain (IPR003439) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251286 control chromosomes (i.e., 1 heterozygote; gnomAD v2.1 Exomes dataset). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.4097T>A has been reported in the literature in at least two compound heterozygous individuals affected with Cystic Fibrosis (e.g., Krenkova_2012, Levy_2016, Geurts_2020, Raraigh_2022). These data indicate that the variant is likely to be associated with disease. At least one unpublished preprint reports experimental evidence evaluating an impact on protein function, finding that the variant results in <10% of normal chloride channel conductance relative to wild type (e.g., Bihler_2023, bioRxiv, no PMID). The following publications have been ascertained in the context of this evaluation (PMID: 32084388, 23276700, 26671754, 35527187). Three submitters have reported clinical-significance assessments for this variant to ClinVar after 2014; two submitters classified the variant as pathogenic and one submitter classified it as uncertain significance. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | May 15, 2017 | - - |
Pathogenic, reviewed by expert panel | research | CFTR2 | Jan 10, 2020 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at