7-117530899-G-A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_Very_Strong

The NM_000492.4(CFTR):c.274G>A(p.Glu92Lys) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,447,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense, splice_region

Scores

Splicing: ADA: 0.9962

Clinical Significance

Pathogenic reviewed by expert panel P:13

Conservation

PhyloP100: 9.52

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a helix (size 27) in uniprot entity CFTR_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

PP5

Variant 7-117530899-G-A is Pathogenic according to our data. Variant chr7-117530899-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7181.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr7-117530899-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.274G>A	p.Glu92Lys	missense_variant, splice_region_variant	Exon 4 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.274G>A	p.Glu92Lys	missense_variant, splice_region_variant	Exon 4 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1447030

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

720964

show subpopulations

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:

0.00000182

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:13

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:8

Jun 13, 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.274G>A (p.Glu92Lys) variant involves the alteration of a conserved nucleotide located in the ABC transporter type 1, transmembrane domain (InterPro). The variant affects the first nucleotide in exon 4. 4/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 117032 control chromosomes. The variant has been reported in numerous CF alleles in the literature, and functional in vitro analysis has shown the variant to result in defective CFTR processing and <10% chloride transport (Sosnay_2013, Van Goor_2014) compared to WT. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. -

Jul 26, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E92K pathogenic mutation (also known as c.274G>A and 406G>A), located in coding exon 4 of the CFTR gene, results from a G to A substitution at nucleotide position 274. This change occurs in the first base pair of coding exon 4. The glutamic acid at codon 92 is replaced by lysine, an amino acid with some similar properties. This mutation was identified in the homozygous state in a child with cystic fibrosis, elevated sweat chloride level, pancreatic sufficiency and history of Pseudomonas infection (Stanke F et al. J Med Genet. 2008;45(1):47-54). This variant has been reported in multiple individuals with an elevated sweat chloride level in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 07/26/2022). This variant has <25% of wild type quantity and <10% of wild type function in The Clinical and Functional TRanslation of CFTR (CFTR2) database (available at http://cftr2.org. Accessed 07/26/2022; Sosnay PR et al. Nat Genet. 2013;45(10):1160-7). In addition, in vitro functional studies in FRT cells with this variant showed little to no mature CFTR protein (Van Goor F et al. J Cyst Fibros. 2014;13(1):29-36) . Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Mar 04, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PM3_VSTR,PS3,PM5,PM2_SUP,PP3,PP4 -

Jul 22, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Feb 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 92 of the CFTR protein (p.Glu92Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with cystic fibrosis, pancreatic insufficiency and congenital bilateral absence of the vas deferens (CBAVD) (PMID: 10875853, 18178635, 29504914). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 7181). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CFTR function (PMID: 18306312, 23891399, 23924900, 28448979). For these reasons, this variant has been classified as Pathogenic. -

Sep 14, 2016

Counsyl

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 17, 2017

CFTR2

Significance: Pathogenic

Review Status: reviewed by expert panel

Collection Method: research

- -

not provided

Pathogenic:2

Jul 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 04, 2017

Clinical Genetics and Genomics, Karolinska University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder

Pathogenic:1

Mar 17, 2017

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Nov 18, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystic fibrosis;C5924204:CFTR-related disorder

Pathogenic:1

Jan 29, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

when the variant is in trans with another CF-causing variation, can either result in CF or in a CFTR-RD -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.94

BayesDel_addAF

Pathogenic

0.54

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.81

.;D;.;.;T;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.88

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D;D;D

M_CAP

Pathogenic

0.90

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.5

.;M;.;.;.;M

PrimateAI

Uncertain

0.75

PROVEAN

Uncertain

-4.0

D;D;.;.;D;.

REVEL

Pathogenic

0.90

Sift

Pathogenic

0.0

D;D;.;.;D;.

Sift4G

Pathogenic

0.0

D;D;.;.;D;.

Polyphen

1.0

.;D;.;.;.;.

Vest4

0.94

MutPred

0.95

.;Gain of MoRF binding (P = 0.0121);Gain of MoRF binding (P = 0.0121);Gain of MoRF binding (P = 0.0121);Gain of MoRF binding (P = 0.0121);Gain of MoRF binding (P = 0.0121);

MVP

1.0

MPC

0.014

ClinPred

0.99

GERP RS

5.7

Varity_R

0.96

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.88

SpliceAI score (max)

0.17

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

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