rs199791061

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP5

The NM_000492.4(CFTR):c.2173G>A(p.Glu725Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:9O:1

Conservation

PhyloP100: 7.15

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-117592340-G-A is Pathogenic according to our data. Variant chr7-117592340-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53448.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=8, Pathogenic=2, not_provided=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.2173G>A	p.Glu725Lys	missense_variant	Exon 14 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.2173G>A	p.Glu725Lys	missense_variant	Exon 14 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000854

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000103

AC:

AN:

251228

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135832

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.0000868

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000185

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000113

AC:

165

AN:

1461790

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000137

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000854

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000140

Hom.:

Bravo

AF:

0.0000793

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000906

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:9Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3

Feb 19, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.2173G>A; p.Glu725Lys variant (rs199791061) has been described in patients with cystic fibrosis, but without strong evidence for pathogenicity (des Georges 2004, Kanavakis 2003). This variant has also been reported in the heterozygous state in one individual with suboptimal fertility and one individual affected with hypertrypsinemia (Gene 2008, Larriba 2005). This variant is also reported in ClinVar (Variation ID: 53448). This variant is found in the general population with an overall allele frequency of 0.009% (28/282634 alleles) in the Genome Aggregation Database. The glutamic acid at codon 725 is moderately conserved, computational analyses predict that this variant is deleterious (REVEL: 0.77). However, given the lack of clinical and functional data, the significance of the p.Glu725Lys variant is uncertain at this time. References: Des Georges M et al. High heterogeneity of CFTR mutations and unexpected low incidence of cystic fibrosis in the Mediterranean France. J Cyst Fibros. 2004 Dec;3(4):265-72. Gene G et al. N-terminal CFTR missense variants severely affect the behavior of the CFTR chloride channel. Hum Mutat. 2008 May;29(5):738-49. Kanavakis E et al. Cystic fibrosis in Greece: molecular diagnosis, haplotypes, prenatal diagnosis and carrier identification amongst high-risk individuals. Clin Genet. 2003 May;63(5):400-9. Larriba S et al. Molecular evaluation of CFTR sequence variants in male infertility of testicular origin. Int J Androl. 2005 Oct;28(5):284-90. -

Jan 06, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 27, 2016

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cystic fibrosis

Pathogenic:1Uncertain:2Other:1

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

May 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

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 725 of the CFTR protein (p.Glu725Lys). This variant is present in population databases (rs199791061, gnomAD 0.02%). This missense change has been observed in individual(s) with cystic fibrosis (PMID: 12752573, 15698946, 18306312). ClinVar contains an entry for this variant (Variation ID: 53448). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CFTR protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Jul 22, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E725K variant (also known as c.2173G>A), located in coding exon 14 of the CFTR gene, results from a G to A substitution at nucleotide position 2173. The glutamic acid at codon 725 is replaced by lysine, an amino acid with similar properties. This variant has been detected in individuals diagnosed with cystic fibrosis (des Georges M et al. J. Cyst. Fibros., 2004 Dec;3:265-72, Claustres M et al. Hum Mutat, 2017 10;38:1297-1315, Kanavakis E et al. Clin Genet, 2003 May;63:400-9). In addition, the alteration has been reported in patients with idiopathic chronic pancreatitis, primary sclerosing cholangitis, suboptimal fertility, and hypertrypsinemia (Zou WB et al. Clin Transl Gastroenterol, 2018 11;9:204, Pall H et al. J Pediatr, 2007 Sep;151:255-9, Larriba S et al. Int J Androl, 2005 Oct;28:284-90, Gené GG et al. Hum Mutat, 2008 May;29:738-49).). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

CFTR-related disorder

Pathogenic:1Uncertain:2

Mar 26, 2018

CFTR-France

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

May 08, 2018

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Uncertain:1

Jan 03, 2025

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

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.2173G>A (p.Glu725Lys) results in a conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0001 in 251338 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.0001 vs 0.013), allowing no conclusion about variant significance. c.2173G>A has been reported in the literature as a non-informative genotype (second allele and/or zygosity not specified or second allele of uncertain/questionable pathogenicity) in individuals with atypical and variably expressive sub-phenotypic or sub clinical presentations of Cystic Fibrosis (CF) (example, Gene_2008, Kanavakis_2003, Larriba_2005, Girardet_2015, Pall_2007, Audrezat_2008, Hekim_2016, Grangeia_2018). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis.Multiple reports of co-occurrences in cis with another pathogenic variant in the CFTR gene (legacy name c.1766+5G>A, also named c.1898+5G>A) with a fully informative genotype in obligate carrier parents and/or CF-chromosomes (Girardet_2015, des Georges_2004) have been reported (ACMG BP2). Additionally, an instance of a co-occurring pathogenic variant in a different gene (SPINK1 c.194+2T>C), in an individual affected with Chronic Pancreatitis (Zou_2018) has also been reported (ACMG BP5). These reports provide supporting evidence for a benign/non-causative role in settings of autosomal recessive Cystic Fibrosis or autosomal dominant SPINK1 associated Pancreatitis. One publication qualitatively reports that double mutants including the variant had no effect on maturation of the CFTR protein (Chen_2002). However, this study does not allow convincing conclusions about the variant effect in isolation. The following publications have been ascertained in the context of this evaluation (PMID: 18687795, 12361483, 18306312, 24762087, 29589582, 27195969, 12752573, 16128988, 17719933, 25735457, 11950844, 30420730, 15698946). ClinVar contains an entry for this variant (Variation ID: 53448). Based on the evidence outlined above, although this variant meets at-least two supportive criteria given in the ACMG classification guidance, namely BP2 and BP5, the variant was classified as VUS-possibly benign. -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

May 21, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.090

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

D;.;T;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Pathogenic

0.31

MetaRNN

Uncertain

0.53

D;D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Uncertain

2.0

M;.;.;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-1.5

N;.;N;.

REVEL

Pathogenic

0.77

Sift

Uncertain

0.012

D;.;D;.

Sift4G

Uncertain

0.0030

D;.;D;.

Polyphen

0.96

D;.;.;.

Vest4

0.84

MVP

0.99

MPC

0.0064

ClinPred

0.28

GERP RS

4.6

Varity_R

0.23

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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