rs199791061
Positions:
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
NM_000492.4 missense
Scores
7
8
4
Clinical Significance
Conservation
PhyloP100: 7.15
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]
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: {not_provided=1, Likely_pathogenic=1, Uncertain_significance=7, Pathogenic=2}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.2173G>A | p.Glu725Lys | missense_variant | 14/27 | ENST00000003084.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CFTR | ENST00000003084.11 | c.2173G>A | p.Glu725Lys | missense_variant | 14/27 | 1 | NM_000492.4 | P2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000854 AC: 13AN: 152154Hom.: 0 Cov.: 32
GnomAD3 genomes
?
AF:
AC:
13
AN:
152154
Hom.:
Cov.:
32
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000103 AC: 26AN: 251228Hom.: 0 AF XY: 0.000140 AC XY: 19AN XY: 135832
GnomAD3 exomes
AF:
AC:
26
AN:
251228
Hom.:
AF XY:
AC XY:
19
AN XY:
135832
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.000113 AC: 165AN: 1461790Hom.: 0 Cov.: 32 AF XY: 0.000118 AC XY: 86AN XY: 727200
GnomAD4 exome
AF:
AC:
165
AN:
1461790
Hom.:
Cov.:
32
AF XY:
AC XY:
86
AN XY:
727200
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000854 AC: 13AN: 152272Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8AN XY: 74456
GnomAD4 genome
?
AF:
AC:
13
AN:
152272
Hom.:
Cov.:
32
AF XY:
AC XY:
8
AN XY:
74456
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
TwinsUK
AF:
AC:
0
ALSPAC
AF:
AC:
2
ExAC
?
AF:
AC:
11
EpiCase
AF:
EpiControl
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:8Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 06, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Feb 19, 2021 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 27, 2016 | - - |
Cystic fibrosis Pathogenic:1Uncertain:2Other:1
not provided, no classification provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | - | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 22, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 28, 2022 | 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. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 29, 2022 | 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 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. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
CFTR-related disorder Pathogenic:1Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | 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. - |
Pathogenic, criteria provided, single submitter | curation | CFTR-France | Mar 26, 2018 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | May 08, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 29, 2023 | 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 report(s) 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). Ten submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Multiple submitters reported the variant with conflicting assessments (VUS, n=7; P/LP, n=3). Most submitters cite overlapping evidence utilized in the context of this evaluation. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Uncertain
D;.;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M;.;.;.
MutationTaster
Benign
D;D
PrimateAI
Benign
T
PROVEAN
Benign
N;.;N;.
REVEL
Pathogenic
Sift
Uncertain
D;.;D;.
Sift4G
Uncertain
D;.;D;.
Polyphen
D;.;.;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at