rs121908799

Positions:

• chr7-117592217-AAA-AG

Variant summary

Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1 PS1 PM2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.2051_2052delAAinsG​(p.Lys684fs) variant causes a frameshift, missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★★). Another nucleotide change resulting in same amino acid change has been previously reported as Pathogenicin Lovd. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K684R) has been classified as Pathogenic. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CFTR NM_000492.4 frameshift, missense
• Clinical Significance: Pathogenic reviewed by expert panel P:12
• Conservation: PhyloP100: 1.79

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 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS1: Transcript NM_000492.4 (CFTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in Lovd
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117592218-AA-G is Pathogenic according to our data. Variant chr7-117592218-AA-G is described in ClinVar as [Pathogenic]. Clinvar id is 35837.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.2051_2052delAAinsG	p.Lys684fs	frameshift_variant, missense_variant	14/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11	c.2051_2052delAAinsG	p.Lys684fs	frameshift_variant, missense_variant	14/27	1	NM_000492.4	ENSP00000003084.6

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:12

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:7

Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 27, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 11, 2019	NM_000492.3(CFTR):c.2051_2052delAAinsG(K684Sfs*38, aka 2183AA>G) 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.2051_2052delAAinsG(K684Sfs*38, aka 2183AA>G) is based on the following criteria: The variant causes a premature termination codon that is expected to be targeted by nonsense-mediated mRNA decay and is reported in individuals with the relevant phenotype. Please note: this variant was assessed in the context of healthy population screening.‚Äã -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	May 31, 2023	The inherited c.2051_2052delAAinsG (p.Lys684Serfs*38) indel variant (also known as 2183AA>G) identified in exon 14 (of 27) of the CFTR gene has been reported in multiple affected individuals in the literature ((PMID: 23974870, CFTR2 database: https://cftr2.org). The variant alters the wild-type translational reading frame and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. This variant has been reported in the ClinVar database as Pathogenic by multiple independent laboratories [Variation ID: 35837]. Based on the available evidence, the inherited c.2051_2052delAAinsG (p.Lys684Serfs*38) frameshift variant identified in the CFTR gene is reported as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 27, 2011	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 04, 2021	The c.2051_2052delAAinsG pathogenic mutation, located in coding exon 14 of the CFTR gene, results from the deletion of two nucleotides and insertion of one nucleotide causing a translational frameshift with a predicted alternate stop codon (p.K684Sfs*38). This mutation was first described in trans with p.F508del in an individual with a clinical diagnosis of cystic fibrosis; however, specific phenotype information was not provided (Verlingue C et al. Prenat. Diagn., 1993 Dec;13:1143-8). This alteration has been associated with elevated sweat chloride levels, pulmonary symptoms, and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7; Petrova NV et al. Genes (Basel), 2020 05;11:). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

not provided Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 05, 2022	The CFTR c.2051_2052delinsG; p.Lys684SerfsTer38 variant (rs121908799), commonly known as 2183AA -> G, has been reported in multiple patients diagnosed with the pancreatic insufficient form of cystic fibrosis (Bozon 1994, Kilinc 2000, Capurso 2009, Ooi 2012, Sosnay 2013). This variant is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting two nucleotides and inserting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on the available information, this variant is considered to be pathogenic. References: Bozon D et al. Identification of four new mutations in the cystic fibrosis transmembrane conductance regulator gene: I148T, L1077P, Y1092X, 2183AA-->G. Hum Mutat. 1994 3(3):330-2. PMID: 7517268. Capurso G et al. Phenotype expression in a case of adult cystic fibrosis caused by an extremely rare compound heterozygous genotype (2183AA>G/2789+5G>A). Pancreas. 2009 Jul;38(5):599-601. PMID: 19550280. Kilinc M et al. Genotype-phenotype correlation in three homozygotes for the cystic fibrosis mutation 2183AA-->G shows a severe phenotype. J Med Genet. 2000 37(4):307-9. PMID: 10819640. Ooi CY et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 Sep;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 Oct;45(10):1160-7. PMID: 23974870. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 12, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 05, 2023	This frameshift variant alters the translational reading frame of the CFTR mRNA and causes the premature termination of CFTR protein synthesis. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been first reported in trans with p.F508del variant in a child with a clinical diagnosis of cystic fibrosis (PMID: 7513889 (1993)). Later one, this variant was described to be associated with different range of CF and CF-related phenotypes (PMIDs: 7517268 (1994), 20460946 (2010), 22658665 (2012), 22020151 (2012), 23974870 (2013), 33613790 (2021). This variant has even been detected in an asymptomatic individual (PMID: 28603918 (2017)). However, when the variant is homozygous state or compound heterozygous with another CF-causing variant it results in a sever CF phenotype with severe pancreatic insufficiency as the most common clinical feature shown (PMID: 10819640 (2000)). Based on the available information, this variant is classified as pathogenic. -

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

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs121908799; hg19: chr7-117232272;