rs121908767

Positions:

chr7-117610592-CAGTGAT-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PM4PP5_Very_Strong

The NM_000492.4(CFTR):c.3067_3072del(p.Ile1023_Val1024del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.0000105 in 1,613,340 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

CFTR
NM_000492.4 inframe_deletion

Scores

Not classified

Clinical Significance

Pathogenic reviewed by expert panel P:17

Conservation

PhyloP100: 5.95

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a domain ABC transmembrane type-1 2 (size 296) in uniprot entity CFTR_HUMAN there are 53 pathogenic changes around while only 8 benign (87%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000492.4.

PP5

Variant 7-117610592-CAGTGAT-C is Pathogenic according to our data. Variant chr7-117610592-CAGTGAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 38480.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117610592-CAGTGAT-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.3067_3072del	p.Ile1023_Val1024del	inframe_deletion	19/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.3067_3072del	p.Ile1023_Val1024del	inframe_deletion	19/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1
	ENST00000456270.1 linkuse as main transcript	n.178-5609_178-5604del		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251080

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135708

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

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:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000109

AC:

AN:

1461258

Hom.:

AF XY:

0.0000110

AC XY:

AN XY:

726950

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000179

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:

0.00000720

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:17

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:9

Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 29, 2018	- -
Pathogenic, reviewed by expert panel	research	CFTR2	Sep 24, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 04, 2020	c.3067_3072del has been observed in multiple patients presenting with cystic fibrosis in whom a second disease-associated variant was identified. This variant (rs397508492) is rare (<0.1%) in a large population dataset (gnomAD: 7/251080 total alleles; 0.002788%; no homozygotes). Additionally, seven submitters in ClinVar classify this variant as either pathogenic or likely pathogenic. We consider this variant to be pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 03, 2023	This variant, c.3067_3072del, results in the deletion of 2 amino acid(s) of the CFTR protein (p.Ile1023_Val1024del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs397508492, gnomAD 0.01%). This variant has been observed in individual(s) with cystic fibrosis or congenital absence of the vas deferens (PMID: 7516234, 12394343, 15287992, 22020151, 22627569). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as 3199del6 or 3195del6. ClinVar contains an entry for this variant (Variation ID: 38480). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 4 unrelated patients with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PM2_SUP, PM3_VSTR, PM4, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Dec 04, 2019	NM_000492.3(CFTR):c.3067_3072del6(aka 3199del6) is classified as pathogenic in the context of cystic fibrosis. Sources cited for classification include the following: PMID 15371908, 10798368, 12172395, 15371907, 11668613, 8707304, 15371903, 15017334, 15638824, 7516234, 22020151, 18456578, 12394343 and 21679131. Classification of NM_000492.3(CFTR):c.3067_3072del6(aka 3199del6) is based on the following criteria: This is a well-established pathogenic variant in the literature that has been observed more frequently in patients with clinical diagnoses than in healthy populations. Please note: this variant was assessed in the context of healthy population screening. -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 11, 2023	The c.3067_3072delATAGTG pathogenic mutation (also known as 3199del6, 3195del6, and p.I1023_V1024del) is located in coding exon 19 of the CFTR gene. This pathogenic mutation results from an in-frame deletion of 6 nucleotides at positions 3067 to 3072. This results in the deletion of an isoleucine and a valine residue between codons 1023 and 1024. This mutation was first reported in an individual with cystic fibrosis (CF) in trans with a frameshift alteration (Claustres M et al. Hum. Mol. Genet., 1994 Feb;3:371). In another study, this mutation was identified in trans with a nonsense alteration in an individual with CF with meconium ileus, pulmonary symptoms, pancreatic sufficiency, and elevated sweat chloride levels (Buyse IM et al. Genet. Med.;6:426-30). In a cohort of unrelated French Canadian individuals with CF, 21 of 22 individuals bearing this mutation and another severe CFTR alteration were pancreatic insufficient (Ruchon AF et al. Genet. Med., 2005 Mar;7:210-1). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 18, 2016	Variant summary: The c.3067_3072delATAGTG (a.k.a. 3199del6) in CFTR gene is an in-frame deletion that expected to remove Ile1023 and Val1024 from the CFTR protein. Mutation Taster predicts deleterious outcome. The variant is absent from the large and broad cohorts of the ExAC project. The variant of interest has been identified in multiple affected individuals presented with CF and was referred as causative mutation in peer-reviewed publications. At least one reputable clinical laboratory/diagnostic center classified the variant as Pathogenic. Taking together, the variant was classified as Pathogenic. -

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jun 16, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 13, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 06, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 18, 2017	- -

CFTR-related disorder

Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 17, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jul 19, 2024	The CFTR c.3067_3072del6 variant is predicted to result in an in-frame deletion (p.Ile1023_Val1024del). This variant, also referred to as 3199del6 using legacy nomenclature, has been reported to be causative for cystic fibrosis (see, for example, Buyse et al. 2004. PubMed ID: 15371908; Monaghan et al. 2004. PubMed ID: 15371907; Castellani et al. 2008. PubMed ID: 18456578; Sosnay PR et al 2013. PubMed ID: 23974870; https://cftr2.org). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD and is interpreted as pathogenic by multiple laboratories in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/38480/). Based on the available evidence, we classify this variant 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

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 11, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over