7-117666903-C-T
Variant summary
Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong
The NM_000492.4(CFTR):c.4243-5C>T 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 0.000244 in 1,613,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000492.4 splice_region, splice_polypyrimidine_tract, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.4243-5C>T | 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.4243-5C>T | splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00134 AC: 204AN: 152152Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000400 AC: 100AN: 249978Hom.: 0 AF XY: 0.000296 AC XY: 40AN XY: 135192
GnomAD4 exome AF: 0.000130 AC: 190AN: 1461600Hom.: 0 Cov.: 31 AF XY: 0.000110 AC XY: 80AN XY: 727124
GnomAD4 genome AF: 0.00134 AC: 204AN: 152270Hom.: 0 Cov.: 32 AF XY: 0.00124 AC XY: 92AN XY: 74448
ClinVar
Submissions by phenotype
not specified Benign:5
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Aug 15, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Aug 25, 2015 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Genomic Medicine (IGM) Clinical Laboratory, Nationwide Children's Hospital | Nov 14, 2017 | BP4, BP6; This alteration is predicted to be tolerated by multiple functional prediction tools, and was reported as a benign/likely benign alteration by a reputable source (ClinVar or other correspondence from a clinical testing laboratory). - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 27, 2023 | Variant summary: CFTR c.4243-5C>T alters a 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. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0004 in 249978 control chromosomes (gnomAD). This frequency is slightly lower than the frequency estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0004 vs 0.013), suggesting a benign role for this variant. c.4243-5C>T has been reported in literature in patients with CF and CFTR-related phenotypes without strong evidence for pathogenicity (Zhou_2013, Brennan_2016, Kharrazi_2015, Pagin_2016, Ratkiewicz_2017). In a patient with CFTR-related metabolic syndrome, biallelic pathogenic variants were detected (Prach_2013), supporting for benign outcome. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
Cystic fibrosis Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 07, 2018 | 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, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 17, 2020 | - - |
Benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Hereditary pancreatitis Benign:1
Likely benign, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 30, 2021 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 27, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at