rs199791061

chr7-117592340-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:8 O:1
• 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]

ACMG classification

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: {Pathogenic=2, Uncertain_significance=7, Likely_pathogenic=1, not_provided=1}.

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: 13 AN: 152154 Hom.: 0 Cov.: 32

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: 26 AN: 251228 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135832

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.: 0 Cov.: 32 AF XY: 0.000118 AC XY: 86 AN XY: 727200

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: 13 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74456

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.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:8 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 27, 2016	- -
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. -

Cystic fibrosis Pathogenic:1 Uncertain:2 Other:1

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. -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -

CFTR-related disorder Pathogenic:1 Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 08, 2018	- -
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	- -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Pathogenic	0.32
Cadd	Uncertain	25
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D;.;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.53	D;D;D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.0	M;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
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	T
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

Other links and lift over

dbSNP: rs199791061; hg19: chr7-117232394; COSMIC: COSV50060811; COSMIC: COSV50060811;