rs121908748

Positions:

• chr7-117590440-G-A
• chr7-117590440-G-C
• chr7-117590440-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.1766+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,600,060 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 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CFTR NM_000492.4 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic practice guideline P:21 O:1
• Conservation: PhyloP100: 9.27

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.01935629 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117590440-G-A is Pathogenic according to our data. Variant chr7-117590440-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7168.Status of the report is practice_guideline, 4 stars. Variant chr7-117590440-G-A is described in Lovd as [Pathogenic]. Variant chr7-117590440-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.1766+1G>A		splice_donor_variant		ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.1766+1G>A		splice_donor_variant		1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152036 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000589

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000321 AC: 8 AN: 249234 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135034

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000709

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 161 AN: 1448024 Hom.: 0 Cov.: 30 AF XY: 0.000101 AC XY: 73 AN XY: 720180

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000144

Gnomad4 OTH exome AF: 0.0000336

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152036 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74250

Gnomad4 AFR AF: 0.0000241

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: 0.0000589

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000610 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000467 AC: 4

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:21 Other:1

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:10 Other:1

Pathogenic, practice guideline	curation	American College of Medical Genetics and Genomics (ACMG)	Mar 03, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 15, 2022	The c.1766+1G>A intronic pathogenic mutation (also known as c.1898+1G>A) results from a G to A substitution one nucleotide after coding exon 13 of the CFTR gene. This mutation was reported in two unrelated individuals with cystic fibrosis who had pancreatic insufficiency, pulmonary disease, and abnormal sweat chloride levels; both individuals were also heterozygous for p.F508del (Strong TV et al. Hum. Mutat., 1992;1:380-7). Two other mutations at the same nucleotide position, c.1766+1G>C and c.1766+1G>T, have been reported in individuals with cystic fibrosis (Cuppens H et al. Genomics, 1993 Dec;18:693-7; Crawford J et al. Hum. Mutat., 1995;5:101-2; Petrova NV et al. Genes (Basel), 2020 May;11(5):554). 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 a disease-causing mutation. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 20, 2019	NM_000492.3(CFTR):c.1766+1G>A(aka 1898+1G>A) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.1766+1G>A(aka 1898+1G>A) is based on the following criteria: The variant is located at a canonical splice site, is expected to disrupt gene function and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1992	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jan 29, 2020	Disease-causing CFTR variant (previously reported for this patient by mass spectrometry genotyping). See www.CFTR2.org for phenotype information. -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 01, 2019	Variant summary: CFTR c.1766+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. The variant allele was found at a frequency of 3.6e-05 in 275450 control chromosomes (gnomAD). The variant, c.1766+1G>A (also known as 1898+1G>A) is a common disease variant and has been reported in the literature and databases in numerous individuals affected with Cystic Fibrosis (see e.g. Sosnay 2013). There are 415 patients listed with this variant in the CFTR2 database, and 94% of these patients are pancreatic insufficient. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and both of them classified the variant as pathogenic. The variant has been also classified as pathogenic by the CFTR2 database expert panel. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 25, 2023	This sequence change affects a donor splice site in intron 13 of the CFTR gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs121908748, gnomAD 0.007%). Disruption of this splice site has been observed in individuals with cystic fibrosis (PMID: 1284540, 18456578, 22658665, 23974870). This variant is also known as 1898+1G>A. ClinVar contains an entry for this variant (Variation ID: 7168). Studies have shown that disruption of this splice site results in skipping of exon 13 (also known as exon 12), but is expected to preserve the integrity of the reading-frame (PMID: 1284540). For these reasons, this variant has been classified as Pathogenic. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jul 21, 2023	The CFTR c.1766+1G>A variant disrupts a canonical splice-donor site and interferes with normal CFTR mRNA splicing. This variant has been shown to maintain the translation reading frame of the CFTR mRNA; however, skipping of exon 13 (also known as exon 12) removes a portion of the gene important for its function (PMID: 1284540 (1992)). In the published literature, this variant has been reported in individuals with Cystic Fibrosis (PMID: 1284540 (1992), 23974870 (2013), 23276700 (2013), 26708955 (2016), 28544683 (2017), and 32429104 (2020)). The variant is described in online databases as being pathogenic and CF-causing (CFTR2 (https://cftr2.org/)). The frequency of this variant in the general population, 0.00016 (8/50402 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, this variant is classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 21, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

CFTR-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 20, 2019	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 30, 2024	The CFTR c.1766+1G>A variant is predicted to disrupt the GT donor site and interfere with normal splicing. This variant, also referred to as c.1898+1G>A using legacy nomenclature, has been reported in the compound heterozygous state in patients with cystic fibrosis (Strong et al. 1992. PubMed ID: 1284540; Castellani et al. 2008. PubMed ID: 18456578). RNA analysis from patient nasal epithelium indicated that this variant results in skipping of exon 12 (Strong et al. 1992. PubMed ID: 1284540). This variant is reported in 0.0070% of alleles in individuals of European (Non-Finnish) descent in gnomAD. In summary, the c.1766+1G>A variant is categorized as pathogenic. -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Jan 28, 2019

The CFTR c.1766+1G>A variant (rs121908748), also known as 1898+1G>A, is reported in the literature in multiple individuals affected with pancreatic insufficient cystic fibrosis (Sosnay 2013, Strong 1992). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 7168), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant disrupts the canonical splice donor site of intron 12, which is likely to negatively impact gene function. Based on available information, this variant is considered to be pathogenic. References: Sosnay PR et al. Defining the disease liability of variants in the cystic fibrosis transmembrane conductance regulator gene. Nat Genet. 2013 Oct;45(10):1160-7. Strong TV et al. Characterization of an intron 12 splice donor mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Hum Mutat. 1992;1(5):380-7. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

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- -

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

Feb 09, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	D;D
GERP RS		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.86		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908748; hg19: chr7-117230494;