rs121908779

Positions:

• chr7-117592089-GCTCAAAACT-GA

Variant summary

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

The NM_000492.4(CFTR):​c.1923_1931delinsA​(p.Ser641ArgfsTer5) variant causes a frameshift 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
• Clinical Significance: Pathogenic reviewed by expert panel P:9
• Conservation: PhyloP100: 7.38

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 7-117592090-CTCAAAACT-A is Pathogenic according to our data. Variant chr7-117592090-CTCAAAACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 38735.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1923_1931delinsA	p.Ser641ArgfsTer5	frameshift_variant	14/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1923_1931delinsA	p.Ser641ArgfsTer5	frameshift_variant	14/27	1	NM_000492.4	P2

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

Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 09, 2019	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Oct 16, 2019	Disease-causing CFTR variant. See www.CFTR2.org for phenotype information. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2022	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2020	- -

not specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Sep 06, 2017

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. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

-

- -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

May 20, 2019

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Jan 22, 2024

- -

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: rs121908779; hg19: chr7-117232144;