rs371315549
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_000492.4(CFTR):c.274-6T>C variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000833 in 1,587,290 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000492.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.274-6T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.274-6T>C | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.000460 AC: 70AN: 152198Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000467 AC: 117AN: 250412Hom.: 0 AF XY: 0.000539 AC XY: 73AN XY: 135342
GnomAD4 exome AF: 0.000872 AC: 1252AN: 1434974Hom.: 1 Cov.: 28 AF XY: 0.000852 AC XY: 610AN XY: 715630
GnomAD4 genome ? AF: 0.000460 AC: 70AN: 152316Hom.: 0 Cov.: 32 AF XY: 0.000443 AC XY: 33AN XY: 74482
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:5
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 19, 2016 | Variant summary: The c.274-6T>C in CFTR gene is an intronic variant that affects a non-conserved nucleotide located at a position not widely known to affect splicing. 5/5 in silico tools predict no significant effects on splicing and these predictions been confirmed by in vitro/vivo studies (Raynal , 2013). Variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 0.0005 (59/114809 chrs tested) predominantly in individuals of Non-Finnish European ancestry. Although the observed frequency does not exceed the maximal expected allele frequency of a disease causing allele (0.006), it is more than carrier frequency of all known splice acceptor mutations in ExAC cohort, indicating it is rare polymorphism. The variant was reported in several CF-RD spectrum patients without strong evidence for pathogenicity as well as in unaffected controls. Clinical diagnostic centers classify variant as Benign/VUS without evidence to independently evaluate. Taking together, the variant was classified as Likely Benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 02, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 07, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | CFTR: BP4 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 07, 2020 | This variant is associated with the following publications: (PMID: 32429104, 10571949, 10601093, 10746558, 11938439, 21499205, 23381846, 21708286, 20717170, 15858154, 21198395, 7691344, 21520337, 25087612, 25781545, 25525159, 17020467, 15758663) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 09, 2018 | - - |
Cystic fibrosis Benign:6
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 22, 2019 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Likely benign, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | Feb 14, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | Aug 22, 2023 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 07, 2019 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Apr 25, 2016 | Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Not reported. No information available. Gene not associated to pt disease. - |
CFTR-related disorder Uncertain:1
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. - |
Hereditary pancreatitis Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Aug 03, 2021 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at