rs397508325

Positions:

• chr7-117592150-CCTAA-C

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.1986_1989del​(p.Thr663ArgfsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,686 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CFTR NM_000492.4 frameshift
• Clinical Significance: Pathogenic reviewed by expert panel P:7
• 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 7-117592150-CCTAA-C is Pathogenic according to our data. Variant chr7-117592150-CCTAA-C is described in ClinVar as [Pathogenic]. Clinvar id is 53421.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117592150-CCTAA-C is described in Lovd as [Pathogenic]. Variant chr7-117592150-CCTAA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1986_1989del	p.Thr663ArgfsTer8	frameshift_variant	14/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1986_1989del	p.Thr663ArgfsTer8	frameshift_variant	14/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461686 Hom.: 0 AF XY: 0.00000688 AC XY: 5 AN XY: 727140

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: 0.00000719

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: reviewed by expert panel

Submissions by phenotype

Cystic fibrosis Pathogenic:5

Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Nov 08, 2023	This sequence change creates a premature translational stop signal (p.Thr663Argfs*8) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with CFTR-related conditions (PMID: 7689898). This variant is also known as 2118del4. ClinVar contains an entry for this variant (Variation ID: 53421). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, reviewed by expert panel	research	CFTR2	Mar 17, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Feb 25, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	May 10, 2024	The c.1986_1989delAACT pathogenic mutation, located in coding exon 14 of the CFTR gene, results from a deletion of 4 nucleotides at nucleotide positions 1986 to 1989, causing a translational frameshift with a predicted alternate stop codon (p.T663Rfs*8). This alteration has been reported in the compound heterozygous state with a second CFTR alteration in an individual from a cystic fibrosis cohort (Chevalier-Porst F et al. Hum. Mol. Genet., 1993 Jul;2:1071-2). Of note, this alteration is also known as 2118del4 in published 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 specified Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

May 16, 2019

The CFTR c.1986_1989delAACT; p.Thr663fs variant (rs397508325), also known as 2118del4, is reported in the literature in the compound heterozygous state in individuals affected with cystic fibrosis (UMD-CFTR mutation database, Chevalier-Porst 1993). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 53421), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. This variant causes a frameshift by deleting 4 nucleotides, 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: Link to UMD-CFTR mutation database: http://www.umd.be/CFTR/4DACTION/WV/3070 Chevalier-Porst F et al. Identification of three rare frameshift mutations in exon 13 of the cystic fibrosis gene: 1918delGC, 2118del4 and 2372del8. Hum Mol Genet. 1993 Jul;2(7):1071-2. -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.29		Position offset: -21

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

Publications

LitVar

Other links and lift over

dbSNP: rs397508325; hg19: chr7-117232204;