rs141158996
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000492.4(CFTR):c.2490+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,537,676 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )
Consequence
CFTR
NM_000492.4 splice_donor, intron
NM_000492.4 splice_donor, intron
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 9.04
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 4.7, offset of 4, new splice context is: tagGTatac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-117592658-G-A is Pathogenic according to our data. Variant chr7-117592658-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7175.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117592658-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.2490+1G>A | splice_donor_variant, intron_variant | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000105 AC: 2AN: 190386Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 102242
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GnomAD4 exome AF: 0.0000173 AC: 24AN: 1385468Hom.: 0 Cov.: 31 AF XY: 0.0000175 AC XY: 12AN XY: 684508
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GnomAD4 genome 0.0000131 AC: 2AN: 152208Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74362
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:14
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:8
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 07, 2016 | Variant summary: The CFTR c.2490+1G>A variant involves the alteration of a conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant, and 5/5 splicing algorithms predict the variant to abolish the canonical splice donor site. This variant was found in 2/109598 control chromosomes at a frequency of 0.0000182, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been cited in numerous classic CF patients in the literature in trans with pathogenic variants, including deltaF508. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic/likely pathogenic. Taken together, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | - - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 09, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 31, 2019 | - - |
| Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 18, 2022 | The c.2490+1G>A intronic pathogenic mutation (also known as 2622+1G>A) results from a G to A one nucleotide after coding exon 14 of the CFTR gene. This mutation was first described in an affected two-year-old with cystic fibrosis, including pancreatic insufficiency and pulmonary disease, in conjunction with p.F508del (Audrézet MP et al. Hum. Mol. Genet., 1993 Jan;2:51-4). This mutation is associated with elevated sweat chloride levels, pancreatic insufficiency, and an increased rate of Pseudomonas infection (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 21, 2023 | This sequence change affects a donor splice site in intron 14 of the CFTR gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs141158996, gnomAD 0.002%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 7683952, 9239681, 12815607, 20059485, 23974870). This variant is also known as 2622+1G>A. ClinVar contains an entry for this variant (Variation ID: 7175). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Counsyl | Jul 21, 2015 | - - |
CFTR-related disorder Pathogenic:3
| Pathogenic, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jul 31, 2019 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 20, 2024 | The CFTR c.2490+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, also known as c.2622+1G>A, has been repeatedly documented as pathogenic in individuals with cystic fibrosis (Audrezet et al. 1993. PubMed ID: 7683952; Scotet et al. 2003. PubMed ID: 12815607; Sosnay et al. 2013, PubMed ID: 23974870; https://cftr2.org/mutation/scientific/2622%252B1G-%253EA). Multiple clinical diagnostic labs have interpreted this variant as pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/7175/). This variant is reported in 0.0021% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Variants that disrupt the consensus splice donor site in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. - |
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
not provided Pathogenic:2
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 08, 2020 | The CFTR c.2490+1G>A variant (rs141158996), also known as 2622+1G>A, has been identified in many individuals affected with pancreatic insufficient forms of cystic fibrosis (see link for CFTR2 database, Audrezet 1993, Dorfman 2010, Krenkova 2013, Scotet 2003, Sosnay 2013) and at least one individual with congenital bilateral absence of the vas deferens (De Braekeleer 1996). It is also reported as pathogenic in ClinVar (Variation ID: 7175). This variant abolishes the splice donor site of intron 13 and is predicted to alter splicing (Alamut v.2.11). Based on available information, this variant is considered pathogenic. References: Link to CFTR2 database: https://cftr2.org/ Audrezet M et al. Identification of 12 novel mutations in the CFTR gene. Hum Mol Genet. 1993 Jan;2(1):51-4. De Braekeleer M et al. Mutations in the cystic fibrosis gene in men with congenital bilateral absence of the vas deferens. Mol Hum Reprod. 1996 Sep;2(9):669-77. Dorfman R et al. Do common in silico tools predict the clinical consequences of amino-acid substitutions in the CFTR gene? Clin Genet. 2010 May;77(5):464-73. Krenkova P et al. Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. J Cyst Fibros. 2013 Sep;12(5):532-7. Scotet V et al. Comparison of the CFTR mutation spectrum in three cohorts of patients of Celtic origin from Brittany (France) and Ireland. Hum Mutat. 2003 Jul;22(1):105. Sosnay P et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 16, 2024 | PP3, PM2, PM3_very_strong, PVS1 - |
Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 13, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 3
DS_DL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at