rs80224560

Variant names:

• chr7-117602868-G-A
• rs80224560
• NM_000492.4:c.2657+5G>A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000492.4(CFTR):​c.2657+5G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.0000782 in 1,610,282 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign 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 0.000079 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000078 (1 hom.)
• Consequence: CFTR NM_000492.4 splice_region, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic practice guideline P:32 O:1
• Conservation: PhyloP100: 5.83

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-117602868-G-A is Pathogenic according to our data. Variant chr7-117602868-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 38497.Status of the report is practice_guideline, 4 stars. Variant chr7-117602868-G-A is described in Lovd as [Pathogenic]. Variant chr7-117602868-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4	c.2657+5G>A		splice_region_variant, intron_variant	Intron 16 of 26	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.2657+5G>A		splice_region_variant, intron_variant	Intron 16 of 26	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000756 AC: 19 AN: 251474 Hom.: 0 AF XY: 0.0000809 AC XY: 11 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000782 AC: 114 AN: 1458108 Hom.: 1 Cov.: 29 AF XY: 0.0000758 AC XY: 55 AN XY: 725668

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000911

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000789 AC: 12 AN: 152174 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74342

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.0000793

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:32 Other:1

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:15 Other:1

Nov 05, 2018

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

Nov 21, 2018

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 08, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Feb 19, 2020

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. -

Mar 14, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Mar 07, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2657+5G>A variant in CFTR represents 0.3-0.48% of alleles identified in in dividuals with cystic fibrosis (McKone 2003, Watson 2004, Boeck 2014). RNA studi es have shown that the c.2657+5G>A causes aberrant splicing, resulting in the sk ipping of exons 15 and 16 and leading to a significantly decreased expression of CFTR (Masvidal 2014, Sharma 2014). Accordingly, this variant is considered as a class V variant, leading to reduced amounts of functioning CFTR protein. It has been identified in 19/126716 European chromosomes by the Genome Aggregation Dat abase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs80224560). Although thi s variant has been seen in the general population, its frequency is low enough t o be consistent with a recessive carrier frequency. Moreover, the c.2657+5G>A va riant was classified as Pathogenic on March 3, 2004 by the American College of M edical Genetics and Genomics (ClinVar SCV000071401.2). In summary, the c.2657+5G >A variant meets criteria to be classified as pathogenic for CFTR-related disord ers, including cystic fibrosis, in an autosomal recessive manner based upon its frequency in affected individuals and functional evidence. ACMG/AMP Criteria app lied (Richards 2015): PS3, PS4. -

Nov 12, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000492.3(CFTR):c.2657+5G>A(aka 2789+5G>A) is classified as pathogenic in the context of cystic fibrosis and is associated with a non-classic form of disease. Sources cited for classification include the following: PMID: 23974870. Classification of NM_000492.3(CFTR):c.2657+5G>A(aka 2789+5G>A) 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. -

Jul 22, 2020

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

0102 - Loss of function is a known mechanism of disease in this gene and is associated with cystic fibrosis (MIM#219700). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0210 - Splice site variant proven to affect splicing of the transcript with a known effect on protein sequence. Mini gene assays and ex vivo studies demonstrated that the variant results in the skipping of exon 16 (PMID: 24129438). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD (v2) <0.01 for a recessive condition (20 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has very strong previous evidence of pathogenicity in unrelated individuals. The variant has been widely reported as pathogenic in autosomal recessive cystic fibrosis (MIM#219700). It is considered to be a class V variant, resulting in partially impaired protein function and is associated with a milder phenotype (ClinVar, PMID: 24129438). (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Mar 03, 2004

American College of Medical Genetics and Genomics (ACMG)

Significance: Pathogenic

Review Status: practice guideline

Collection Method: curation

- -

Apr 04, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.2657+5G>A variant (rs80224560), also known as 2789+5G>A, is reported in the medical literature in multiple individuals with cystic fibrosis (CF), with about half of those individuals diagnosed with the pancreatic sufficient form of CF (Sosnay 2013). This variant is reported in ClinVar (Variation ID: 38497), and is found in the general population with an overall allele frequency of 0.007% (20/282870 alleles) in the Genome Aggregation Database. Computational analyses (Alamut v.2.11) predict that this variant alters splicing, and functional studies reveal that the variant leads to the production of an aberrant transcript, while reducing full-length transcripts to 4% of normal levels (Highsmith 1997). Based on available information, this variant is considered to be pathogenic. References: Highsmith WE Jr et al. Identification of a splice site mutation (2789 +5 G > A) associated with small amounts of normal CFTR mRNA and mild cystic fibrosis. Hum Mutat. 1997; 9(4):332-8. PMID: 9101293. 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. -

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 4 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: PS1_SUP, PS3, PM2_SUP, PM3_STR, PP3, PP4 -

May 12, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2657+5G>A intronic pathogenic mutation (also known as 2789+5G>A) results from a G to A substitution 5 nucleotides after coding exon 16 in the CFTR gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This alteration was reported in 88 individuals with cystic fibrosis, of which 61 were compound heterozygous with p.F508del; these individuals had elevated sweat chloride levels, pulmonary symptoms, normal gastrointestinal function, and approximately 60% were pancreatic insufficient (Dugu&eacute;p&eacute;roux I et al. Eur. Respir. J., 2005 Mar;25:468-73). In another study, individuals who were homozygous for this mutation in a consanguineous family presented with mild obstructive lung disease, abnormal sweat chloride levels, and pancreatic sufficiency. In addition, mRNA levels in the nasal epithelium from these individuals were 4% of wild-type (Highsmith WE et al. Hum. Mutat., 1997;9:332-8). An in vitro minigene assay had concordant findings and showed that this mutation reduces protein expression to <10% of wild type (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. -

Dec 13, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 16 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 (rs80224560, gnomAD 0.01%). This variant has been observed in individual(s) with cystic fibrosis (PMID: 12767731, 17347447, 19550280, 21520337, 22020151, 23751316, 23974870, 25122143). 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 c.2789+5G>A. ClinVar contains an entry for this variant (Variation ID: 38497). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24129438, 25066652). For these reasons, this variant has been classified as Pathogenic. -

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GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Dec 03, 2017

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:9

-

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

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CFTR: PM3:Very Strong, PM2, PS1:Supporting, PS3:Supporting -

Aug 22, 2022

Revvity Omics, Revvity

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 27, 2022

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 23, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 14, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.2657+5G>A variant has been reported in the published literature in the homozygous state or compound heterozygous state with other CF variants in individuals with CF and CF-related disorders (PMIDs: 12767731 (2003), 15371902 (2004), 15738290 (2005), 17347447 (2007), 22658665 (2012), 24440181 (2014), 24129438 (2014), 25122143 (2015)). Functional studies have described this variant as a Class V variant, causing aberrant splicing, exon 16 skipping, and partial loss of the CFTR protein (PMIDs: 9101293 (1997), 24129438 (2014), 25066652 (2014)). The frequency of this variant in the general population, 0.00078 (9/11610 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is consistent with pathogenicity. Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper CFTR mRNA splicing. Based on the available information, this variant is classified as pathogenic. -

Dec 06, 2017

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 15, 2018

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2657+5G>A variant in the CFTR gene (also reported as c.2789+5G>A due to alternate nomenclature) has been reported previously as a pathogenic variant, with a variant frequency of 0.38% among individuals with clinically diagnosed cystic fibrosis (McKone et al., 2003; Watson et al., 2004; De Boeck et al., 2014). Functional studies have shown that c.2657+5G>A causes aberrant splicing and results in the skipping of exon 16. Also, very low levels of CFTR are expressed in mutant cell lines (Masvidal et al., 2014; Sharma et al., 2014). The c.2657+G>A variant was not observed at any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.2657+5G>A as a pathogenic variant. -

CFTR-related disorder Pathogenic:2

Apr 04, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CFTR c.2657+5G>A variant is predicted to interfere with splicing. This variant (also known as 2789+5G>A in the literature) is predicted and functionally proven to result in aberrant splicing and skipping of exon 16 due to disruption of the splice donor site (Masvidal et al. 2014. PubMed ID: 24129438). This variant has been previously reported to be causative for cystic fibrosis (e.g., Duguépéroux and Braekeleer. 2005. PubMed ID: 15738290; Masvidal et al. 2014. PubMed ID: 24129438; Supplementary data, Sosnay et al. 2013. PubMed ID: 23974870). This variant is reported in 0.015% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified Pathogenic:1

Feb 26, 2018

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.2657+5G>A alters a conserved 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 abolishes a 5' splicing donor site. Three predict the variant weakens a 5' donor site. At least one publication reports experimental evidence that this variant affects mRNA splicing. The variant allele was found at a frequency of 7.2e-05 in 277224 control chromosomes. The c.2657+5G>A variant has been reported in the literature in multiple individuals affected with Cystic Fibrosis. These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

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Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary pancreatitis Pathogenic:1

Apr 06, 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

May 24, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Mar 26, 2024

Baylor 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	-0.28
CADD	Uncertain	24
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.98
SpliceAI score (max)		0.93		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.93		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs80224560; hg19: chr7-117242922;