7-117590444-G-T

Variant names:

• chr7-117590444-G-T
• rs121908796
• NM_000492.4:c.1766+5G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 8P and 1B. PP5_Very_Strong BP4

The NM_000492.4(CFTR):​c.1766+5G>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00000375 in 1,598,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: CFTR NM_000492.4 splice_region, intron
• Scores: Splicing: ADA: 0.5251
• Clinical Significance: Pathogenic reviewed by expert panel P:18
• Conservation: PhyloP100: 3.78
• Publications: 21 publications found

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]

CFTR Gene-Disease associations (from GenCC):

• cystic fibrosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
• congenital bilateral absence of vas deferens

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hereditary chronic pancreatitis

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PP5: Variant 7-117590444-G-T is Pathogenic according to our data. Variant chr7-117590444-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 48685.Status of the report is reviewed_by_expert_panel, 3 stars.
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.23). . 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.1766+5G>T		splice_region_variant, intron_variant	Intron 13 of 26	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1766+5G>T		splice_region_variant, intron_variant	Intron 13 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000241 AC: 6 AN: 249012 AF XY: 0.0000296

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1446438 Hom.: 0 Cov.: 30 AF XY: 0.00000417 AC XY: 3 AN XY: 719434

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33132

American (AMR) AF: 0.00 AC: 0 AN: 44238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25556

East Asian (EAS) AF: 0.0000764 AC: 3 AN: 39288

South Asian (SAS) AF: 0.00 AC: 0 AN: 85958

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51740

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5586

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1101472

Other (OTH) AF: 0.0000168 AC: 1 AN: 59468

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000286219), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74284

African (AFR) AF: 0.00 AC: 0 AN: 41458

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67910

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.0000341 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:9

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

Dec 25, 2023

Department of Urology, First Affiliated Hospital of Nanjing Medical University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Dec 04, 2019

Myriad Genetics, Inc.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000492.3(CFTR):c.1766+5G>T(aka 1898+5G>T) is classified as likely pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 23089694, 8213163, 25580864, 16202790, 7543385, 23381846, 12874665 and 18456578. Classification of NM_000492.3(CFTR):c.1766+5G>T(aka 1898+5G>T) is based on the following criteria: This variant 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.

Mar 05, 2025

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.1766+5G>T alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant weakens a 5' donor site and one predicts the variant abolishes a 5' splicing donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing (Zielenski_1995). The variant allele was found at a frequency of 2.4e-05 in 249042 control chromosomes. c.1766+5G>T has been reported in the literature in multiple individuals affected with Cystic Fibrosis (e.g., Zielenski_1005, Alper_2003, Liu_2015). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <10% of normal activity (Zielenski_1995). The following publications have been ascertained in the context of this evaluation (PMID: 12874665, 25580864, 7543385). ClinVar contains an entry for this variant (Variation ID: 48685). Based on the evidence outlined above, the variant was classified as pathogenic.

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Mar 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 13 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 likely results in a shortened protein product. This variant is present in population databases (rs121908796, gnomAD 0.04%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 7543385, 10925568, 12874665, 18456578). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It is commonly reported in individuals of East Asian ancestry (PMID: 18456578). This variant is also known as c.1898+5G>T. ClinVar contains an entry for this variant (Variation ID: 48685). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 12, but is expected to preserve the integrity of the reading-frame (PMID: 7543385, 23381846). For these reasons, this variant has been classified as Pathogenic.

Oct 16, 2019

Johns Hopkins Genomics, Johns Hopkins University

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disease-causing CFTR variant. See www.CFTR2.org for phenotype information.

Feb 13, 2025

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1766+5G>T intronic pathogenic mutation results from a G to T substitution 5 nucleotides after coding exon 13 in the CFTR gene. This alteration was identified in an individual with high sweat chloride levels, respiratory complications and pancreatic insufficiency who carried this mutation in trans with a complex allele (Alper OM et al J Formos Med Assoc. 2003;102(5):287-291). This alteration might account for almost 30% of carrier alleles in the Chinese/Taiwanese population (Zielenski et al Annu Rev Genet. 1995; 29:777-807). This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 02/13/2025). This variant has <10% of wild type quantity in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 02/13/2025). Of note, this alteration is also known as c.1898+5G>T in published literature. This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. In-vitro functional studies indicate an alternate transcript is formed 77-80% of the time due to exon skipping and an in-frame deletion of exon 12 (Raynal et al Hum Mutat 2013; 34(5):774-784). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.

Feb 10, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1766+5G>T (NM_000492.3 c.1766+5G>T) variant in CFTR has been reported in 1 homozygous and 3 compound heterozygous Asian individuals with clinical features of cystic fibrosis (Zielenski 1995, Leung 2016, Shen 2016). This variant has be en identified in 0.023% (2/8,562) of East Asian chromosomes by the Exome Aggrega tion Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs121908796). This variant is located in the 3' splice region. Computational tools suggest a possib le impact to splicing consistent with the +5 position being predominantly a G nu cleotide. In summary, the clinical significance of the c.1766+5G>T variant is li kely pathogenic based upon biallelic case observations, suggestive splicing impa ct and low frequency in the general population.

not provided Pathogenic:4

Nov 27, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1766+5G>T variant (rs121908796), also known as 1898+5G>T, is reported in the literature in the homozygous or compound heterozygous state in multiple individuals affected with cystic fibrosis, and is a common variant in East Asian patients (Chen 2012, Liu 2015, Shen 2016, Sontag 2005, Xu 2017). This variant is reported in ClinVar (Variation ID: 48685), and is only observed on eight alleles in the Genome Aggregation Database, indicating it is not a common polymorphism. This is an intronic variant in a highly conserved nucleotide, and computational analyses (Alamut Visual Plus v.1.5.1) predict that this variant may impact splicing by weakening the nearby canonical donor splice site. In vitro functional assays show that this variant results in skipping of exon 12 (Raynal 2013). Based on available information, this variant is considered to be pathogenic. References: Chen CH et al. Acute appendicitis mimicking intestinal obstruction in a patient with cystic fibrosis. J Formos Med Assoc. 2012;111(10):580-583. PMID: 23089694. Liu Y et al. Characterization of gene mutations and phenotypes of cystic fibrosis in Chinese patients. Respirology. 2015;20(2):312-318. PMID: 25580864. Raynal C et al. A classification model relative to splicing for variants of unknown clinical significance: application to the CFTR gene. Hum Mutat. 2013;34(5):774-784. PMID: 23381846. Shen Y et al. Clinical Phenotypes and Genotypic Spectrum of Cystic Fibrosis in Chinese Children. J Pediatr. 2016;171:269-76.e1. PMID: 26826884. Sontag MK et al. Two-tiered immunoreactive trypsinogen-based newborn screening for cystic fibrosis in Colorado: screening efficacy and diagnostic outcomes. J Pediatr. 2005;147(3 Suppl):S83-S88. PMID: 16202790. Xu J et al. Four case reports of Chinese cystic fibrosis patients and literature review. Pediatr Pulmonol. 2017;52(8):1020-1028. PMID: 28608624.

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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:2

Feb 17, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;For recessive disorders, detected in trans with a pathogenic variant.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.

Cystic fibrosis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR-related disorder Pathogenic:1

Sep 30, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1766+5G>T variant is predicted to interfere with splicing. This variant, also referred to as c.1898+5G>A using legacy nomenclature, has been reported in the homozygous and compound heterozygous state in patients with cystic fibrosis (Zielenski et al 1995. PubMed ID: 7543385; Castellani C et al 2008. PubMed ID: 18456578; Shen Y et al 2020. PubMed ID: 32761997 ). Another substitution at this same nucleotide position, c.1766+5G>A, has also been reported as causative for cystic fibrosis (des Georges et al 2004. PubMed ID: 15698946; Raynal C et al 2013. PubMed ID: 23381846). Both variants have been reported to result in exon 12 skipping due to alteration of splicing at the exon 12/intron 12 boundary region (Zielenski et al 1995. PubMed ID: 7543385; Raynal C et al 2013. PubMed ID: 23381846). This variant is reported in 0.040% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117230498-G-T). This variant is interpreted as pathogenic.

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Feb 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.23
CADD	Benign	20
DANN	Benign	0.92
PhyloP100		3.8
Mutation Taster		=3/97	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.53
dbscSNV1_RF	Benign	0.67
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.69		Position offset: -5

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

Other links and lift over

dbSNP: rs121908796; hg19: chr7-117230498;