rs139379077
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Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_000492.4(CFTR):c.2620-15C>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00192 in 1,613,194 control chromosomes in the GnomAD database, including 26 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 0.0022 ( 3 hom., cov: 33)
Exomes 𝑓: 0.0019 ( 23 hom. )
Consequence
CFTR
NM_000492.4 splice_polypyrimidine_tract, intron
NM_000492.4 splice_polypyrimidine_tract, intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.425
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 Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.86).
BP6
?
Variant 7-117602811-C-G is Benign according to our data. Variant chr7-117602811-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35844.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=3, Likely_benign=6}. Variant chr7-117602811-C-G is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00189 (2767/1460900) while in subpopulation MID AF= 0.0331 (191/5766). AF 95% confidence interval is 0.0293. There are 23 homozygotes in gnomad4_exome. There are 1494 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
BS2
?
High Homozygotes in GnomAd4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.2620-15C>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.2620-15C>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.00218 AC: 332AN: 152176Hom.: 4 Cov.: 33
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GnomAD3 exomes AF: 0.00272 AC: 685AN: 251464Hom.: 8 AF XY: 0.00296 AC XY: 402AN XY: 135908
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GnomAD4 exome AF: 0.00189 AC: 2767AN: 1460900Hom.: 23 Cov.: 30 AF XY: 0.00206 AC XY: 1494AN XY: 726818
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GnomAD4 genome ? AF: 0.00217 AC: 330AN: 152294Hom.: 3 Cov.: 33 AF XY: 0.00239 AC XY: 178AN XY: 74456
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:12
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Cystic fibrosis Uncertain:2Benign:5
Uncertain significance, criteria provided, single submitter | clinical testing;curation | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 18, 2011 | - - |
Benign, criteria provided, single submitter | clinical testing | Johns Hopkins Genomics, Johns Hopkins University | May 25, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
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, PP4, BS2 - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 26, 2014 | This alteration is classified as 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 | Mendelics | May 28, 2019 | - - |
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 19, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 19, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2024 | CFTR: BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 14, 2019 | This variant is associated with the following publications: (PMID: 19017867, 20100616, 16251901, 16128988, 27264265, 9521595, 24272871, 9272157, 29174009, 25900089, 29807875, 28408918, 26500004, 28040058, 28546993, 27884173, 10875853, 15070876) - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 29, 2016 | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
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). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled 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 | Apr 04, 2021 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
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