rs397508380

Positions:

• chr7-117592637-AT-A

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.2472del​(p.Asn825ThrfsTer5) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,390,544 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: 0.0000014 (0 hom.)
• Consequence: CFTR NM_000492.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5 O:1
• Conservation: PhyloP100: 7.24

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 7-117592637-AT-A is Pathogenic according to our data. Variant chr7-117592637-AT-A is described in ClinVar as [Pathogenic]. Clinvar id is 53494.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4	c.2472del	p.Asn825ThrfsTer5	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.2472del	p.Asn825ThrfsTer5	frameshift_variant	14/27	1	NM_000492.4	ENSP00000003084	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000519 AC: 1 AN: 192696 Hom.: 0 AF XY: 0.00000970 AC XY: 1 AN XY: 103096

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1390544 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 687226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000331

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: 0.00

Gnomad4 OTH exome AF: 0.0000174

GnomAD4 genome Cov.: 32

Alfa AF: 0.000112 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Cystic fibrosis Pathogenic:2 Other:1

not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 14, 2020	The c.2472delT pathogenic mutation, located in coding exon 14 of the CFTR gene, results from a deletion of one nucleotide at nucleotide position 2472, causing a translational frameshift with a predicted alternate stop codon (p.N825Tfs*5). 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. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 14, 2020	For these reasons, this variant has been classified as Pathogenic. This variant has been observed in individual(s) with cystic fibrosis (PMID: 7687986). In at least one individual the data is consistent with the variant being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as CF2603/4delT in the literature. ClinVar contains an entry for this variant (Variation ID: 53494). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Asn825Thrfs*5) 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). -

CFTR-related disorder Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Mar 17, 2017

- -

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

Feb 09, 2022

- -

Bronchiectasis with or without elevated sweat chloride 1 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs397508380; hg19: chr7-117232691;