rs201386642
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBS2_Supporting
The NM_000492.4(CFTR):c.2506G>T(p.Asp836Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000406 in 1,612,886 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00038 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00041 ( 2 hom. )
Consequence
CFTR
NM_000492.4 missense
NM_000492.4 missense
Scores
9
5
5
Clinical Significance
Conservation
PhyloP100: 9.06
Genes affected
CFTR (HGNC:1884): (CF transmembrane conductance regulator) This gene encodes a member of the ATP-binding cassette (ABC) transporter superfamily. The encoded protein functions as a chloride channel, making it unique among members of this protein family, and controls ion and water secretion and absorption in epithelial tissues. Channel activation is mediated by cycles of regulatory domain phosphorylation, ATP-binding by the nucleotide-binding domains, and ATP hydrolysis. Mutations in this gene cause cystic fibrosis, the most common lethal genetic disorder in populations of Northern European descent. The most frequently occurring mutation in cystic fibrosis, DeltaF508, results in impaired folding and trafficking of the encoded protein. Multiple pseudogenes have been identified in the human genome. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.19826666).
BS2
High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.2506G>T | p.Asp836Tyr | missense_variant | 15/27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CFTR | ENST00000003084.11 | c.2506G>T | p.Asp836Tyr | missense_variant | 15/27 | 1 | NM_000492.4 | ENSP00000003084 | P2 |
Frequencies
GnomAD3 genomes 0.000382 AC: 58AN: 152010Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000442 AC: 111AN: 251312Hom.: 0 AF XY: 0.000464 AC XY: 63AN XY: 135828
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GnomAD4 exome AF: 0.000409 AC: 597AN: 1460760Hom.: 2 Cov.: 30 AF XY: 0.000378 AC XY: 275AN XY: 726772
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GnomAD4 genome 0.000381 AC: 58AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.000403 AC XY: 30AN XY: 74364
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:12Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cystic fibrosis Uncertain:5Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Oct 18, 2017 | - - |
| 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: PM3_STR, PP3, BS3, BP2 - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 30, 2024 | The p.D836Y variant (also known as c.2506G>T), located in coding exon 15 of the CFTR gene, results from a G to T substitution at nucleotide position 2506. The aspartic acid at codon 836 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration was reported in trans with the p.F508del mutation in a newborn with a negative newborn screen and sweat test (Narzi L et al. Clin. Genet., 2007 Jul;72:39-46). In addition, this alteration was identified in an individual who had p.F508del and normal sweat test (de Gracia J et al. Thorax, 2005 Jul;60:558-63), as well as two affected newborns that had two known pathogenic mutations in CFTR (Salinas DB et al. PLoS ONE, 2016 May;11:e0155624); however, the phase is not known. This alteration was also described in study cohorts of cystic fibrosis; however, clinical details were limited (des Georges M et al. J. Cyst. Fibros., 2004 Dec;3:265-72; Schrijver I et al. J Mol Diagn, 2005 May;7:289-99). In CFBE cells, this variant demonstrated 122% of wild type CFTR function (Raraigh KS et al. Am. J. Hum. Genet., 2018 Jun;102:1062-1077). 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 the available evidence, the clinical significance of this variant remains unclear. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
| Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
not provided Pathogenic:1Uncertain:4
| Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 27, 2022 | - - |
| Likely pathogenic, flagged submission | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Nov 13, 2014 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 16, 2020 | The CFTR c.2506G>T; p.Asp836Tyr variant (rs201386642) has been reported in patients with diagnoses or symptoms of CF (des Georges 2004, de Gracia 2005, Schrijver 2005, CFTR2 database). However, p.Asp836Tyr has also been reported in two individuals with pancreatic-insufficient CF (Salinas 2016) who were compound heterozygotes for two known severe pathogenic variants (F508del and 2215insG). The p.Asp836Tyr variant is listed in ClinVar (Variation ID: 53505) and is found in the Latino population with an overall frequency of 0.18% (62/35414 alleles) in the Genome Aggregation Database. The aspartate at codon 836 is highly conserved, and computational algorithms (PolyPhen-2, SIFT) predict that the variant has an impact on the protein. However, the p.Asp836Tyr variant exhibits wildtype chloride channel activity in conductance assays (Raraigh 2018). Due to conflicting information, the clinical significance of the p.Asp836Tyr variant is uncertain at this time. References: CFTR2 database: https://www.cftr2.org/ de Gracia J et al. Genotype-phenotype correlation for pulmonary function in cystic fibrosis. Thorax. 2005 Jul;60(7):558-63. des Georges M et al. High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France. J Cyst Fibros. 2004 Dec;3(4):265-72. Raraigh KS et al. Functional Assays Are Essential for Interpretation of Missense Variants Associated with Variable Expressivity. Am J Hum Genet. 2018 Jun 7;102(6):1062-1077. Salinas D et al. Benign and Deleterious Cystic Fibrosis Transmembrane Conductance Regulator Mutations Identified by Sequencing in Positive Cystic Fibrosis Newborn Screen Children from California. PLoS One. 2016 May 23;11(5):e0155624. Schrijver I et al. Diagnostic testing by CFTR gene mutation analysis in a large group of Hispanics: novel mutations and assessment of a population-specific mutation spectrum. J Mol Diagn. 2005 May;7(2):289-99. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 19, 2017 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Sep 10, 2021 | - - |
not specified Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Mar 06, 2018 | The p.Asp836Tyr variant in CFTR has been reported in 2 individuals with cystic f ibrosis; however it was unclear if a second CFTR variant was found in these indi viduals (des Georges 2004, Schrijver 2005). It was also identified in the compou nd heterozygous state in 4 individuals who had at least one additional pathogeni c variant in CFTR (de Gracia 2005, Narzi 2007, Salinas 2016). In two of these in dividuals, two other pathogenic variants in CFTR were also identified, suggestin g that the p.Asp836Tyr variant may not be the primary cause of disease (Salinas 2016). This variant has also been reported by other clinical laboratories in Cli nVar (Variation ID# 53505) and has been identified in 0.17% (60/34400) of Latino chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinst itute.org; dbSNP rs201386642). Although this variant has been seen in the genera l population, its frequency is not high enough to rule out a pathogenic role. Co mputational prediction tools and conservation analysis do not provide strong sup port for or against an impact to the protein. In summary, due to conflicting evi dence, the clinical significance of the p.Asp836Tyr variant is uncertain. ACMG/A MP Criteria applied: PM3_Strong, BP2. - |
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 23, 2020 | Variant summary: CFTR c.2506G>T (p.Asp836Tyr) 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 0.00044 in 277324 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-classic Cystic Fibrosis (0.00044 vs 0.013), allowing no conclusion about variant significance. The variant, c.2506G>T, has been reported in the literature in compound heterozygosity with deltaF508 in patients with an equivocal diagnosis of CF as evidenced by negative sweat chloride levels and pancreatic sufficiency (example, Narzi_2007, deGracia_2005) as well as in patients with pancreatically insufficient classic CF phenotype who had two other pathogenic CFTR variants that could explain the diagnosis (Salinas_2016). These data provide supportive evidence for a benign role. Furthermore, in a recent study evaluating CFTR function by short circuit current measurement in a cell system, the variant of interest was found to have 121% of WT-CFTR function (Raraigh _2018). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, at-least one of whom has set a final classification as benign while another laboratory has re-classified the variant from likely pathogenic to uncertain significance citing overlapping evidence utilized in the context of this evaluation (Benign, n=1; VUS, n=5). Furthermore, the CFTR2 database reports this variant as not causative of CF. Based on the absence of concrete evidence supporting a disease causing outcome in literature spanning over 15 years as evidence outlined above, the variant is re-classified as benign. - |
Hereditary pancreatitis Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Oct 07, 2021 | - - |
CFTR-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 05, 2024 | The CFTR c.2506G>T variant is predicted to result in the amino acid substitution p.Asp836Tyr. This variant has been reported on the opposite allele (in trans) with p.Phe508del in at least 2 individuals with a negative sweat test (de Gracia et al. 2005. PubMed ID: 15994263; Narzi et al. 2007. PubMed ID: 17594398). This variant has also been reported in an affected individual that carried two additional CFTR pathogenic variants (Salinas et al. 2016. PubMed ID: 27214204) and in a cohort of patients with cystic fibrosis, but no additional studies were performed to help assess its pathogenicity (des Georges et al 2004. PubMed ID: 15698946). In vitro studies in human cell lines suggest that this variant does not impact CFTR protein function (Raraigh et al. 2018. PubMed ID: 29805046). This variant is reported in 0.18% of alleles in individuals of Latino descent in gnomAD and has conflicting interpretations in ClinVar of benign and uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/53505/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;N;.
REVEL
Pathogenic
Sift
Uncertain
D;.;D;.
Sift4G
Pathogenic
D;.;D;.
Polyphen
D;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at