7-117639961-C-T

Variant names:

• chr7-117639961-C-T
• rs75039782
• NM_000492.4:c.3718-2477C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PM2 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic practice guideline P:28 O:1
• 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]

ENSG00000083622 (HGNC:):

ACMG classification

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 rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.3718-2477C>T		intron_variant	Intron 22 of 26	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.3718-2477C>T		intron_variant	Intron 22 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152004 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.000479

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152004 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74220

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000883

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000242 Hom.: 0

Bravo AF: 0.000121

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:28 Other:1

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:13 Other:1

Nov 12, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 04, 2024

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

PS3,PM3(very strong),PM2 -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Mar 03, 2004

American College of Medical Genetics and Genomics (ACMG)

Significance: Pathogenic

Review Status: practice guideline

Collection Method: curation

- -

Dec 30, 2017

Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2022

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

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 -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

May 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Jun 16, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS3, PM2, PM3_Very Strong, PP3 -

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 altered 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 or IVS22+12191. ClinVar contains an entry for this variant (Variation ID: 7166). Studies have shown that this variant results in inclusion of a pseudo-exon, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 7521937). For these reasons, this variant has been classified as Pathogenic. -

Jul 03, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 23, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3718-2477C>T intronic pathogenic mutation (also known as c.3717+12191C>T and 3849+10kbC>T) results from a C to T substitution 2477 nucleotides upstream from coding exon 23 in the CFTR gene. This alteration results in the creation of a partially active splice site and the insertion of 84 additional nucleotides, containing an in-frame stop codon between coding exons 22 and 23 in a majority of CFTR transcripts (Highsmith WE et al. N. Engl. J. Med., 1994 Oct;331:974-80). This leads to a reduced amount of functional CFTR protein (McKone EF et al. Lancet, 2003 May;361:1671-6). This alteration is associated with elevated sweat chloride levels, respiratory symptoms, and pancreatic sufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:9

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 09, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Mar 18, 2022

AiLife Diagnostics, AiLife Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 08, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR: PM3:Very Strong, PM2, PS3:Moderate -

Jul 03, 2022

Athena Diagnostics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jan 24, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 07, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder Pathogenic:2

Aug 31, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 26, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Pathogenic:1

Dec 13, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Nov 01, 2021

Sema4, Sema4

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

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

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystic fibrosis;C5924204:CFTR-related disorder Pathogenic:1

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs75039782; hg19: chr7-117280015;