rs121908779

Variant names:

• chr7-117592090-CTCAAAACT-A
• rs121908779
• NM_000492.4:c.1923_1931delCTCAAAACTinsA

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 19P and 0B. PVS1 PM2 PP2 PP5_Very_Strong

The NM_000492.4(CFTR):​c.1923_1931delCTCAAAACTinsA​(p.Ser641ArgfsTer5) variant causes a frameshift, missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar 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:9
• Conservation: PhyloP100: 7.38
• Publications: 0 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: Pathogenic. The variant received 19 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
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.
• PP5: Variant 7-117592090-CTCAAAACT-A is Pathogenic according to our data. Variant chr7-117592090-CTCAAAACT-A is described in ClinVar as Pathogenic. ClinVar VariationId is 38735.Status of the report is reviewed_by_expert_panel, 3 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000492.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	NM_000492.4	MANE Select	c.1923_1931delCTCAAAACTinsA	p.Ser641ArgfsTer5	frameshift missense	Exon 14 of 27	NP_000483.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CFTR	ENST00000003084.11	TSL:1 MANE Select	c.1923_1931delCTCAAAACTinsA	p.Ser641ArgfsTer5	frameshift missense	Exon 14 of 27	ENSP00000003084.6
	CFTR	ENST00000699602.1		c.1923_1931delCTCAAAACTinsA	p.Ser641ArgfsTer5	frameshift missense	Exon 14 of 27	ENSP00000514471.1
	CFTR	ENST00000426809.5	TSL:5	c.1833_1841delCTCAAAACTinsA	p.Ser611ArgfsTer5	frameshift missense	Exon 13 of 26	ENSP00000389119.1

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:9

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:3

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

Dec 09, 2019

Myriad Genetics, Inc.

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NM_000492.3(CFTR):c.1923_1931del9ins1(S641Rfs*5, aka 2055del9->A) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 9298826, 10798368 and 21416780. Classification of NM_000492.3(CFTR):c.1923_1931del9ins1(S641Rfs*5, aka 2055del9->A) 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.

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.

not provided Pathogenic:2

Nov 28, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.1923_1931delinsA; p.Ser641ArgfsTer5 variant (rs121908779), also known as 2055del9>A, is reported in the literature in two individuals affected with cystic fibrosis, one of whom was a compound heterozygote with another pathogenic variant (Orozco 1997). The CFTR2 database reports pancreatic insufficiency in 93% of individuals carrying the p.Ser641ArgfsTer5 variant with a second pathogenic CFTR variant (see link). This variant is also reported in ClinVar (Variation ID: 38735), but is absent from the Genome Aggregation Database, indicating it is not a common polymorphism. This variant causes a frameshift by deleting nine nucleotides and inserting a single adenosine, 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 pathogenic. References: CFTR2 database: https://cftr2.org Orozco L et al. Two novel frameshift deletions (1924del7, 2055del9-->A) in the CFTR gene in Mexican cystic fibrosis patients. Hum Mutat. 1997;10(3):239-40.

Mar 16, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Pathogenic:1

Sep 06, 2017

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The CFTR c.1923_1931delinsA (p.Ser641ArgfsX5) variant results in a premature termination codon, predicted to cause a truncated or absent CFTR protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (e.g. c.1973_1985delinsAGAAA, p.Arg658fsX4; c.1976delA, p.Asn659fsX4; c.1986_1989delAACT, p.Thr663fsX8). One in silico tool predicts a damaging outcome for this variant. The variant was not found in the control population dataset of ExAC in 120642 control chromosomes. Multiple publications have cited the variant in homozygous and compound heterozygote individuals with CF (predominantly Hispanic)(Orozco_1997, Orozco_1997, Kammesheidt_2006). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.

CFTR-related disorder Pathogenic:1

May 20, 2019

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Jan 22, 2024

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4
Mutation Taster		=0/200	disease causing (fs/PTC)

Splicing

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

Other links and lift over

dbSNP: rs121908779; hg19: chr7-117232144;