chr7-117639961-C-T
Position:
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2PP5_Very_StrongBP4
The NM_000492.4(CFTR):c.3718-2477C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000118 in 152,004 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★★★).
Frequency
Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)
Consequence
CFTR
NM_000492.4 intron
NM_000492.4 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.590
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-117639961-C-T is Pathogenic according to our data. Variant chr7-117639961-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7166.Status of the report is practice_guideline, 4 stars. Variant chr7-117639961-C-T is described in Lovd as [Pathogenic]. Variant chr7-117639961-C-T is described in Lovd as [Pathogenic]. Variant chr7-117639961-C-T is described in Lovd as [Likely_pathogenic].
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.82). . Strength limited to SUPPORTING due to the PP5.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CFTR | NM_000492.4 | c.3718-2477C>T | intron_variant | ENST00000003084.11 | NP_000483.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CFTR | ENST00000003084.11 | c.3718-2477C>T | intron_variant | 1 | NM_000492.4 | ENSP00000003084.6 |
Frequencies
GnomAD3 genomes 0.000118 AC: 18AN: 152004Hom.: 0 Cov.: 33
GnomAD3 genomes
AF:
AC:
18
AN:
152004
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome 0.000118 AC: 18AN: 152004Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74220
GnomAD4 genome
AF:
AC:
18
AN:
152004
Hom.:
Cov.:
33
AF XY:
AC XY:
9
AN XY:
74220
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:27Other:1
Revision: practice guideline
LINK: link
Submissions by phenotype
Cystic fibrosis Pathogenic:11Other:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 28, 2024 | This sequence change falls in intron 22 of the CFTR gene. It does not directly change the encoded amino acid sequence of the CFTR protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs75039782, gnomAD 0.3%). This variant has been observed in individual(s) with cystic fibrosis (CF) and is included in the American College of Medical Genetics panel of CF variants (PMID: 15371902, 23974870, 26631874). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 3849+10kbC>T in intron 19. ClinVar contains an entry for this variant (Variation ID: 7166). Studies have shown that this variant results in inclusion of a pseudo-exon and introduces a premature termination codon (PMID: 7521937). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | curation | Institute of Human Genetics, University of Leipzig Medical Center | Sep 05, 2022 | This variant was identified in 10 unrelated patients 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: PS3, PM2_SUP, PM3_VSTR, PM4, PP4 - |
| not provided, no classification provided | literature only | GeneReviews | - | - - |
| Pathogenic, practice guideline | curation | American College of Medical Genetics and Genomics (ACMG) | Mar 03, 2004 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | Nov 05, 2018 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University | Dec 30, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | Jun 16, 2022 | PS3, PM2, PM3_Very Strong, PP3 - |
| Pathogenic, reviewed by expert panel | research | CFTR2 | Mar 17, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 12, 2019 | NM_000492.3(CFTR):c.3718-2477C>T(aka 3849+10kbC>T) is classified as pathogenic in the context of cystic fibrosis and is associated with non-classic disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.3718-2477C>T(aka 3849+10kbC>T) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. - |
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 03, 1993 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 03, 2022 | The c.3718-2477C>T variant in CFTR (also known as 3849+10kbC>T) has been reported, in the homozygous and compound heterozygous state, in numerous individuals with cystic fibrosis with and without pancreatic insufficiency (selected publications: Abeliovich 1992 PMID: 1384328, Highsmith 1994 PMID: 7521937, Liang 1998 PMID: 9719631, Watson 2004 PMID: 15371902, de Gracia 2005 PMID: 15994263, Duguépéroux 2005 PMID: 15738290, Ooi 2011 PMID: 20923678). It has also been identified in 0.2% (6/3470) of Ashkenazi Jewish chromosomes by gnomAD (http://gnomad.broadinstitute.org). This deep intronic variant was classified as Pathogenic on Mar 17 2017 by the ClinGen-approved CFTR2 expert panel (also pathogenic per practice guideline) (Variation ID 7166). In vitro functional studies have shown that this variant creates a cryptic splice site that causes the creation of a new exon containing an in-frame premature stop codon, the resulting mRNA is predicted to undergo nonsense-mediated decay (Highsmith 1994 PMID: 7521937). In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive cystic fibrosis. ACMG/AMP Criteria applied: PM2_supporting, PM3_Very Strong, PS3. - |
| Pathogenic, criteria provided, single submitter | research | Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital | Oct 04, 2024 | PS3,PM3(very strong),PM2 - |
not provided Pathogenic:10
| Pathogenic, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 20, 2023 | The CFTR c.3718-2477C>T variant (rs75039782), also known as 3717+12191C>T or 3849+10kbC>T, is reported in the literature in individuals affected with pancreatic sufficient cystic fibrosis (Highsmith 1994, McKone 2003, Ooi 2012, Sosnay 2013). This variant is reported in ClinVar (Variation ID: 7166), and is only observed on two alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a weakly conserved nucleotide, but computational analyses (Alamut v.2.11) predict that this variant may impact splicing by creating a novel cryptic donor splice site and activating a nearby cryptic acceptor splice site. Functional assays show that this leads to the abnormal inclusion of intronic sequence, in the form of a new 84bp exon in the CFTR mRNA (Highsmith 1994). The new exon also includes an in-frame termination codon, which is predicted to result in a truncated protein and or absent transcript. Based on available information, this variant is considered to be pathogenic. References: Highsmith WE et al. A novel mutation in the cystic fibrosis gene in patients with pulmonary disease but normal sweat chloride concentrations. N Engl J Med.1994 331(15):974-80. PMID: 7521937 McKone EF et al. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 2003 361(9370):1671-6. PMID: 12767731 Ooi CY et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 11(5):355-62. PMID: 22658665 Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 45(10):1160-7. PMID: 23974870 - |
| Pathogenic, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Mar 18, 2022 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 08, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 24, 2024 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Mar 01, 2022 | CFTR: PM3:Very Strong, PM2, PS3:Moderate - |
| Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jul 03, 2022 | This variant has been reported in affected individuals with Cystic Fibrosis, congenital bilateral absence of the vas deferens, and CFTR related diseases (PMIDs: 23974870 (2013), 24440181 (2014), 28603918 (2017), 28863137 (2017), and 29261177 (2018)). This variant has also been reported to result in aberrant CFTR splicing, specifically the inclusion of an 84-bp pseudo exon containing a premature stop codon (PMIDs: 24440181 (2014) and 28863137 (2017)).This observation is not an independent occurrence and has been identified in the same individual by RCIGM, the other laboratory participating in the GEMINI study. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 09, 2023 | The CFTR c.3718-2477C>T variant (also known as 3849+10kbC>T, c.3717+12191C>T) has been reported in the published literature to induce aberrant CFTR splicing, specifically the inclusion of an 84-bp pseudo exon containing a premature stop codon that reduced amount of normal CFTR mRNA synthesized (PMIDs: 7521937 (1994), 18456578 (2008), 28863137 (2017)). In addition, this variant has been reported in individuals with cystic fibrosis and CFTR-related disorders, typically associated with mild clinical manifestations and pancreatic sufficiency (PMIDs: 7521937 (1994), 8533846 (1995), 12767731 (2003), 15738290 (2005), 28603918 (2017)). This variant is a known CF mutation (PMID: 32404922 (2020), CFTR2 (http://www.cftr2.org/)). Based on the available information, this variant is classified as pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 07, 2022 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
CFTR-related disorder Pathogenic:2
| Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 26, 2017 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 31, 2023 | The CFTR c.3718-2477C>T variant is predicted to interfere with splicing. This variant is also referred to as 3849+10kbC>T or c.3717+12191C>T. This variant has previously been reported to be causative in multiple cystic fibrosis patients with a mild phenotype (Highsmith et al. 1994. PubMed ID: 7521937; McKone et al. 2003. PubMed ID: 12767731; Duguépéroux et al. 2005. PubMed ID: 15738290; Sosnay et al. 2013. PubMed ID: 23974870; cftr2.org) and is included in the American College Medical Genetics (ACMG) panel of CF variants (Watson et al. 2004. PubMed ID: 15371902; Deignan JL et al. 2023. PubMed ID: 37310422). We classify this variant as pathogenic. - |
not specified Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Dec 13, 2017 | Variant summary: The CFTR c.3718-2477C>T variant involves the alteration of a non-conserved deep intronic nucleotide. One in silico tool predicts a disease-causing outcome for this variant. 5/5 splice prediction tools predict a significant impact on splicing. Functional analysis confirms that this variant is associated with an abnormally spliced product (Highsmith_1994). This variant was found in 2/30924 control chromosomes (gnomAD) at a frequency of 0.0000647, which does not exceed the estimated maximal expected allele frequency of a pathogenic CFTR variant (0.0129603). The variant has been reported in multiple CF patients with a mild phenotype, including 3 homozygotes (Duguproux_2005, Gilbert_1995) and was included in the ACMG CFTR list (Watson_2004). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Hereditary pancreatitis Pathogenic:1
| Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 01, 2021 | - - |
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 | Oct 31, 2018 | - - |
Cystic fibrosis;C5924204:CFTR-related disorder Pathogenic:1
| Pathogenic, criteria provided, single submitter | curation | CFTR-France | Jan 29, 2018 | when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at