rs397508397
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong
The NM_000492.4(CFTR):c.2563G>A(p.Val855Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,612,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V855V) has been classified as Likely benign.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.2563G>A | p.Val855Ile | missense_variant | 15/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.2563G>A | p.Val855Ile | missense_variant | 15/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000987 AC: 15AN: 152026Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000159 AC: 40AN: 251318Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135850
GnomAD4 exome AF: 0.0000794 AC: 116AN: 1460640Hom.: 0 Cov.: 31 AF XY: 0.0000881 AC XY: 64AN XY: 726710
GnomAD4 genome ? AF: 0.0000986 AC: 15AN: 152144Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74376
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:2Other:1
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Uncertain significance, 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: PM2_SUP, PM3, BP4 - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 15, 2021 | The p.V855I variant (also known as c.2563G>A), located in coding exon 15 of the CFTR gene, results from a G to A substitution at nucleotide position 2563. The valine at codon 855 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been reported in a cohort of individuals with asthma (Lázaro C et al. Hum. Mutat., 1999;14:510-9), in an individual with a borderline sweat chloride level, nasal polyposis, and malnutrition (Seia M et al. Clin. Biochem., 2009 May;42:611-6), in a cohort of 381 patients with pancreatitis (Keiles S et al. Pancreas, 2006 Oct;33:221-7) and in a cohort of 250 cystic fibrosis patients from Istanbul diagnosed by two positive sweat chloride tests (Atag E et al. Pediatr Pulmonol, 2019 06;54:743-750). Of note, this alteration is commonly reported in conjunction with the p.R74W alteration in CFTR. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on available evidence to date, the clinical significance of this alteration remains unclear. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 19, 2021 | Variant summary: CFTR c.2563G>A (p.Val855Ile) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (InterPro) of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 253420 control chromosomes (gnomAD and publication data). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00016 vs 0.013), allowing no conclusion about variant significance. c.2563G>A has been reported in the literature in individuals affected with Asthma, Pancreatitis, and Cystic Fibrosis (Keiles_2006, Lazaro_1999, Seia_2009, Atag_2019, Bozdogan_2021, Cruz_2021). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. In addition, the variant has been reported to be in cis with R74W (scored VUS by LCA) in multiple individuals. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as uncertain significance until additional information becomes available (ie, clinical and functional studies). - |
Obstructive azoospermia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Institute of Reproductive Genetics, University of Münster | Mar 16, 2022 | - - |
CFTR-related disorders Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 30, 2018 | - - |
Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 15, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at