ClinVar Miner

Submissions for variant NM_000492.4(CFTR):c.2620-6T>C

gnomAD frequency: 0.00038  dbSNP: rs371315682
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Eurofins Ntd Llc (ga) RCV000589355 SCV000342915 uncertain significance not provided 2016-06-09 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001358661 SCV000696913 likely benign not specified 2022-05-23 criteria provided, single submitter clinical testing Variant summary: CFTR c.2620-6T>C alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. These predictions are corroborated by experimental evidence in a minigene assay, in which the variant was reported to have no impact on splicing (e.g. Leman_2018). The variant allele was found at a frequency of 0.00054 in 251668 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Chronic Pancreatitis Risk (0.00054 vs 0.0063), allowing no conclusion about variant significance. c.2620-6T>C has been reported in the literature in individuals screened for CFTR mutations (e.g. Zhou_2013, Schrijver_2005, Lefterova_2016) without evidence for disease causality, including a report of the variant being found in trans with the common pathogenic p.F508Del mutation in a healthy pregnant woman, suggesting that c.2620-6T>C may be benign or a very mild disease allele (e.g.Wallerstein_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, citing the variant as benign/likely benign (n=3) and uncertain significance (n=3). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Center for Human Genetics Tuebingen RCV000589355 SCV000780897 uncertain significance not provided 2018-03-01 criteria provided, single submitter clinical testing
Mendelics RCV000987963 SCV001137484 likely benign Cystic fibrosis 2019-05-28 criteria provided, single submitter clinical testing
Invitae RCV000987963 SCV001722082 benign Cystic fibrosis 2023-12-31 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000987963 SCV001822113 likely benign Cystic fibrosis 2021-07-22 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV001588876 SCV001822114 uncertain significance Congenital bilateral aplasia of vas deferens from CFTR mutation 2021-07-22 criteria provided, single submitter clinical testing
CFTR-France RCV000987963 SCV002573596 benign Cystic fibrosis 2021-01-11 criteria provided, single submitter curation the variant does not result in CFTR-RD neither
Ambry Genetics RCV000987963 SCV002740789 uncertain significance Cystic fibrosis 2024-03-04 criteria provided, single submitter clinical testing The c.2620-6T>C intronic variant results (also known as 2752-6T>C) from a T to C substitution 6 nucleotides upstream from coding exon 16 in the CFTR gene. This variant was identified in a cohort of Hispanic individuals with clinical symptoms of cystic fibrosis; however, complete genotype and phenotype information was not provided (Schrijver I et al. J Mol Diagn, 2005 May;7:289-99). In addition, this variant was identified in a healthy adult African American female in trans with p.F508del (Wallerstein VI et al. Case Rep Genet, 2017 Jan;2017:7281023). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is not predicted to have any significant effect on this splice acceptor site; however, direct evidence is unavailable. Based on available evidence to date, the clinical significance of this alteration remains unclear.
PreventionGenetics, part of Exact Sciences RCV004542716 SCV004774616 likely benign CFTR-related disorder 2023-06-28 criteria provided, single submitter clinical testing This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000589355 SCV001741502 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000589355 SCV001965635 likely benign not provided no assertion criteria provided clinical testing

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