rs201444561
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_000492.4(CFTR):c.2057C>A(p.Ser686Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000942 in 1,613,650 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S686S) has been classified as Likely benign.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.2057C>A | p.Ser686Tyr | missense_variant | 14/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.2057C>A | p.Ser686Tyr | missense_variant | 14/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152166Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000723 AC: 18AN: 248868Hom.: 0 AF XY: 0.0000740 AC XY: 10AN XY: 135064
GnomAD4 exome AF: 0.0000985 AC: 144AN: 1461484Hom.: 1 Cov.: 31 AF XY: 0.000114 AC XY: 83AN XY: 727014
GnomAD4 genome ? AF: 0.0000526 AC: 8AN: 152166Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5AN XY: 74332
ClinVar
Submissions by phenotype
Cystic fibrosis Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Jan 30, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 27, 2022 | This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 686 of the CFTR protein (p.Ser686Tyr). This variant is present in population databases (rs201444561, gnomAD 0.07%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 27131402). ClinVar contains an entry for this variant (Variation ID: 550500). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CFTR protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Sep 05, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 20, 2024 | The p.S686Y variant (also known as c.2057C>A), located in coding exon 14 of the CFTR gene, results from a C to A substitution at nucleotide position 2057. The serine at codon 686 is replaced by tyrosine, an amino acid with dissimilar properties. This variant was identified in an individual with primary sclerosing cholangitis (Sheth S et al. Hum. Genet., 2003 Aug;113:286-92). This alteration was also identified in the homozygous state in an individual of Ashkenazi Jewish origin; however, clinical information was not provided (Schwartz KM et al. J Mol Diagn, 2009 May;11:211-5). In addition, this variant was detected in conjunction with other CFTR variants; however, detailed clinical or phase information was not provided (Zhou L et al. Clin. Chem., 2013 Jul;59:1052-61; Sontag MK et al. J. Pediatr., 2016 08;175:150-158.e1). In one study, this variant was identified in two asymptomatic carriers in conjunction with p.F508del (Claustres M et al. Hum. Mutat., 2017 10;38:1297-1315). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence to date, the clinical significance of this alteration remains unclear. - |
CFTR-related disorders Uncertain:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 26, 2018 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 02, 2023 | Variant summary: CFTR c.2057C>A (p.Ser686Tyr) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) 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 7.2e-05 in 248868 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (7.2e-05 vs 0.013), allowing no conclusion about variant significance. The variant, c.2057C>A, has been reported in the literature in a patient affected with primary sclerosing cholangitis (Sheth_2003), and with pancreatic ductal adenocarcinoma (Zimmermann_2021). The variant was also reported in an individual affected with asthenospermia (Sickkids database), and cystic fibrosis (da Silva Filho_2020), however, no other variants in trans were specified. In addition, the variant was reported without providing an exact clinical phenotype in homozygous state in an individual of Ashkenazi Jewish origin (Schwartz_2009), and in two individuals who also carried other (potentially) causative CFTR variants (phase not specified) (Zhou_2013, Sontag_2016). On the other hand, the variant was found in two asymptomatic compound heterozygotes, with the pathogenic c.1521_1523del (F508del) variant in trans (Claustres_2017). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 28603918, 15784035, 25735457, 19324992, 12783301, 27131402, 23503723, 33747920, 32819855). Severn ClinVar submitters have assessed the variant since 2014, and all submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 20, 2022 | PP3 - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at