7-117592212-CA-C

Position:

• chr7-117592212-CA-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The ENST00000003084.11(CFTR):​c.2052del​(p.Lys684AsnfsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,466 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★★). Synonymous variant affecting the same amino acid position (i.e. T682T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000047 (0 hom.)
• Consequence: CFTR ENST00000003084.11 frameshift
• Clinical Significance: Pathogenic practice guideline P:22 O:1
• Conservation: PhyloP100: -1.56

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 7-117592212-CA-C is Pathogenic according to our data. Variant chr7-117592212-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 38493.Status of the report is practice_guideline, 4 stars. Variant chr7-117592212-CA-C is described in Lovd as [Pathogenic]. Variant chr7-117592212-CA-C is described in Lovd as [Pathogenic]. Variant chr7-117592212-CA-C is described in Lovd as [Pathogenic]. Variant chr7-117592212-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.2052del	p.Lys684AsnfsTer38	frameshift_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.2052del	p.Lys684AsnfsTer38	frameshift_variant	14/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes AF: 0.0000856 AC: 13 AN: 151870 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.000162

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000562 AC: 14 AN: 249012 Hom.: 0 AF XY: 0.0000370 AC XY: 5 AN XY: 135068

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.0000981

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000472 AC: 69 AN: 1461478 Hom.: 0 Cov.: 31 AF XY: 0.0000468 AC XY: 34 AN XY: 727018

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000671

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: 0.0000549

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 151988 Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5 AN XY: 74294

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000106

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:22 Other:1

Revision: practice guideline

Submissions by phenotype

Cystic fibrosis Pathogenic:10 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Nov 20, 2019	NM_000492.3(CFTR):c.2052delA(K684Nfs*38, aka 2184delA) is classified as pathogenic in the context of cystic fibrosis and is associated with the classic form of this disease. Sources cited for classification include the following: PMID 23974870. Classification of NM_000492.3(CFTR):c.2052delA(K684Nfs*38, aka 2184delA) 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. -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 25, 2016	Variant summary: This c.2052delA variant causes a frameshift, which alters the proteins amino acid sequence beginning at position 684 and leads to a premature termination codon 38 amino acids downstream. It is predicted to cause a truncated or absent CFTR protein. Loss-of-function due to mutations in this gene is an established disease mechanism in CF or CFTR-RD. This variant was found in 7/119584 chromosomes from broad and large populations of ExAC at a frequency of 0.0000585, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0129603) in this gene. This variant is widely reported as a common CF-causing variant in literature and databases. The variant has been found in patients with classic CF. Multiple clinical labs/reputable databases call this variant as pathogenic. Taken together, this variant has been classified as a Pathogenic. -
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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 27, 2024	This sequence change creates a premature translational stop signal (p.Lys684Asnfs*38) in the CFTR gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CFTR are known to be pathogenic (PMID: 1695717, 7691345, 9725922). This variant is present in population databases (rs777301769, gnomAD 0.01%). This premature translational stop signal has been observed in individuals with CFTR-related disorders (PMID: 7525963, 18456578, 22658665, 23974870). ClinVar contains an entry for this variant (Variation ID: 38493). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, practice guideline	curation	American College of Medical Genetics and Genomics (ACMG)	Mar 03, 2004	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Feb 17, 2020	Disease-causing CFTR variant. 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	Ambry Genetics	Feb 28, 2022	The c.2052delA pathogenic mutation (also known as 2184delA), located in coding exon 14 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 2052, causing a translational frameshift with a predicted alternate stop codon (p.K684Nfs*38). In one study, this mutation was detected in an individual with bronchiectasis and elevated sweat chloride levels (Jung H et al. Korean J Lab Med, 2011 Jul;31:219-24). This mutation was found in the homozygous state in a child who presented with mild pulmonary findings, an elevated sweat chloride level, and severe pancreatic and hepatic symptoms (Lissens W et al. J. Med. Genet., 1993 May;30:446). This pathogenic mutation is associated with elevated sweat chloride levels, pulmonary manifestations, and pancreatic insufficiency (Sosnay PR et al. Nat. Genet., 2013 Oct;45:1160-7, Supplementary Table). The frequency of this mutation has been estimated at 0.1% in the United States population, but as high as 1.2% in the populations of Belgium and Southern France (Bobadilla JL et al. Hum. Mutat., 2002 Jun;19:575-606). 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:5

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Aug 25, 2022	- -
Pathogenic, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Nov 03, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 31, 2017	The c.2052delA pathogenic variant in the CFTR gene has been reported previously, sometimes using alternate nomenclature (2184delA), either in the homozygous state or in trans with another CFTR variant in multiple individuals with cystic fibrosis (Lissens et al., 1993; Dork et al., 1994; Jung et al., 2011). The c.2052delA variant causes a frameshift starting with codon Lysine 684, changes this amino acid to an Asparagine residue, and creates a premature Stop codon at position 38 of the new reading frame, denoted p.Lys684AsnfsX38. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The c.2052delA variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret c.2052delA as a pathogenic variant. -

CFTR-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 19, 2023	The CFTR c.2052delA variant is predicted to result in a frameshift and premature protein termination (p.Lys684Asnfs*38). This variant, also referred to as c.2183AA>G, has been reported to be causative for cystic fibrosis (Sosnay et al. 2013. PubMed ID: 23974870; cftr2.org). This variant is reported in 0.011% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Frameshift variants in CFTR are expected to be pathogenic. This variant is interpreted as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 28, 2017	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 09, 2018

The CFTR c.2052delA; p.Lys684fs variant (rs121908746), also known as 2184delA, is reported in the literature in a homozygous or compound heterozygous state in multiple individuals affected with the pancreatic insufficient form of cystic fibrosis (Chevalier-Porst 1994, Dork 1994, Jung 2011, Lissens 1993, McKone 2003, Ooi 2012, Sosnay 2013, Watson 2004). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 38493), and is found in the non-Finnish European population with an overall allele frequency of 0.01% (15/124874 alleles) in the Genome Aggregation Database. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be severely pathogenic. References: Chevalier-Porst F et al. Mutation analysis in 600 French cystic fibrosis patients. J Med Genet. 1994 31(7):541-4. Dork T et al. Detection of more than 50 different CFTR mutations in a large group of German cystic fibrosis patients. Hum Genet. 1994 Nov;94(5):533-42. Jung H et al. Heterogeneous spectrum of CFTR gene mutations in Korean patients with cystic fibrosis. Korean J Lab Med. 2011 Jul;31(3):219-24. Lissens W et al. Mild pulmonary, but severe hepatic disease in a cystic fibrosis patient homozygous for a frameshift mutation in the regulatory domain of the CFTR. J Med Genet. 1993 May;30(5):446. McKone EF et al. Effect of genotype on phenotype and mortality in cystic fibrosis: a retrospective cohort study. Lancet. 2003 May 17;361(9370):1671-6. Ooi C. et al. Cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations in pancreatitis. J Cyst Fibros. 2012 11(5):355-62. 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. Watson MS et al. Cystic fibrosis population carrier screening: 2004 revision of American College of Medical Genetics mutation panel. Genet Med. 2004 Sep-Oct;6(5):387-91. -

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

Jan 19, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 23, 2024

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

MGZ Medical Genetics Center

May 09, 2022

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs121908746; hg19: chr7-117232266;