rs145540754

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000492.4(CFTR):c.2079T>G(p.Phe693Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,613,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:1

Conservation

PhyloP100: 0.0260

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09189761).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.2079T>G	p.Phe693Leu	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.2079T>G	p.Phe693Leu	missense_variant	Exon 14 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000263

AC:

AN:

152120

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000966

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000723

AC:

AN:

248958

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135192

show subpopulations

Gnomad AFR exome

AF:

0.000898

Gnomad AMR exome

AF:

0.0000579

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:

0.00

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461578

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727064

show subpopulations

Gnomad4 AFR exome

AF:

0.000866

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000276

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00101

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:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000305

Hom.:

Bravo

AF:

0.000314

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:11Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Sep 06, 2018

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 22, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.2079T>G (p.Phe693Leu) variant has been reported in the published literature in individuals with clinical manifestations consistent with cystic fibrosis (PMIDs: 10970190 (2000), 12167682 (2002), 14685937 (2004), 15858154 (2005), 19017867 (2009)). Functional studies have shown channel function to be normal (PMID: 9736778 (1998), 38388235 (2024)). One study considered clinical manifestations in light of this variant co-occurring with another variant in a different ion channel (i.e. SCNN1B) and/or the diagnosis of protein energy malnutrition (PEM) (PMID: 19017867 (2009)). In addition, another study detected this variant in one reportedly healthy individual of unknown sex/age who also carried a deleterious variant p.W1282X of unknown phase, however, only limited information was available (PMID: 9736778 (1998)). The frequency of this variant in the general population, 0.0012 (28/24270 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -

Jun 06, 2019

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 14, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.2079T>G; p.Phe693Leu variant (rs145540754) is reported in the literature in individuals with cystic fibrosis- like symptoms; however, a second variant was not always detected (Boyne 2000, Mutesa 2009). Functional analyses found this variant did not significantly affect chloride transport (Vankeerberghen 1998). This variant is also reported in ClinVar (Variation ID: 194336). This variant is found in the African/African American population with an allele frequency of 0.12% (28/24270 alleles, including 1 homozygote) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.591). Due to limited information, the clinical significance of the p.Phe693Leu variant is uncertain at this time. References: Boyne J et al. Many deltaF508 heterozygote neonates with transient hypertrypsinaemia have a second, mild CFTR mutation. J Med Genet. 2000 Jul;37(7):543-7. PMID: 10970190. Mutesa L et al. Genetic analysis of Rwandan patients with cystic fibrosis-like symptoms: identification of novel cystic fibrosis transmembrane conductance regulator and epithelial sodium channel gene variants. Chest. 2009 May;135(5):1233-1242. PMID: 19017867. Vankeerberghen A et al. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998 Oct;7(11):1761-9. PMID: 9736778. -

Cystic fibrosis

Uncertain:4Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.F693L variant (also known as c.2079T>G), located in coding exon 14 of the CFTR gene, results from a T to G substitution at nucleotide position 2079. The phenylalanine at codon 693 is replaced by leucine, an amino acid with highly similar properties. This alteration was observed in an individual with cystic fibrosis-like disease; however, a second CFTR alteration was not documented (Mutesa L et al. Chest, 2009 May;135:1233-42). This alteration was also identified in conjunction with p.F508del in an individual with pancreatic insufficient cystic fibrosis; however, the phase was not provided (Boyne J et al. J Med Genet. 2000;37(7):543-7). An in vitro functional study found that this variant did not significantly affect chloride transportation or the maturation of the protein (Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Nov 03, 2022

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.2079T>G (p.Phe693Leu) results in a non-conservative amino acid change located in the regulator domain (IPR025837) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.9e-05 in 253336 control chromosomes (gnomAD and Monaghan_2004), predominantly at a frequency of 0.0009 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Non-Classic Cystic Fibrosis (7.9e-05 vs 0.013), allowing no conclusion about variant significance. c.2079T>G has been reported in the literature in compound heterozygosity with the 5T variant in an individual affected with Non-Classic Cystic Fibrosis and with p.F508del in a compound heterozygous individual with transient hypertrypsinaemia (e.g. Groman_2002, Boyne_2000). It has also been reported as an uninformative genotype (zygosity/second allele not specified) in an individual affected with Cystic Fibrosis, in the heterozygous state in two individuals with CF-like disease who also harbored variants in the SCNN1G and/or SCNN1B genes as well as in a healthy individual in compound heterozygosity with a pathogenic variant (e.g. Vankeerberghen_1998, Schrijver_2005b, Mutesa_2009). In addition, another variant (c.2077T>C) which leads to the same amino acid change as c.2079T>G, has been reported in a CF patient with an alternative cause for the disease phenotype (e.g. Ferec_1995). These reports do not allow any strong conclusions to be made regarding an association between c.2079T>G and disease. In a functional study, the variant did not significantly affect chloride transport ability in comparison to WT, suggesting it has little to no impact on protein function (Vankeerberghen_1998). Eight submitters have provided clinical-significance assessments for this variant to ClinVar after 2014. The majority classified the variant as VUS (n=7) and one classified it as likely benign. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. -

CFTR-related disorder

Uncertain:1

Nov 21, 2022

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The CFTR c.2079T>G variant is predicted to result in the amino acid substitution p.Phe693Leu. This variant has been reported with a minor allele frequency as high as 0.12% in African populations including one homozygous individual (http://gnomad.broadinstitute.org/variant/7-117232300-T-G), and has been reported as likely benign and a variant of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/194336/). The c.2079T>G variant has been reported in a CFTR database with the patient presenting with severe asthma (http://www.genet.sickkids.on.ca/MutationDetailPage.external?sp=1209). A different nucleotide substitution, c.2077T>C, resulting in the same amino acid change (p.Phe693Leu) has been reported in a patient with pancreatic insufficiency (http://www.genet.sickkids.on.ca/MutationDetailPage.external?sp=343). This variant has been reported individuals with cystic fibrosis (Groman et al. 2002. PubMed ID: 12167682; Mutesa et al. 2008. PubMed ID: 19017867), pancreatic insufficient cystic fibrosis (Boyne et al. 2000. PubMed ID: 10970190), and healthy individuals (Vankeerberghen et al. 1998. PubMed ID: 9736778). Functional studies have shown that the p.Phe693Leu variant did not significantly affect chloride transport when compared to wild-type CFTR channels (Vankeerberghen et al. 1998. PubMed ID: 9736778). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.084

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Uncertain

0.51

D;.;T;.

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.69

T;T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.092

T;T;T;T

MetaSVM

Uncertain

0.021

MutationAssessor

Uncertain

2.0

M;.;.;.

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.72

N;.;N;.

REVEL

Uncertain

0.59

Sift

Benign

0.20

T;.;T;.

Sift4G

Benign

0.12

T;.;T;.

Polyphen

0.0

B;.;.;.

Vest4

0.69

MutPred

0.64

Loss of methylation at K688 (P = 0.0951);.;.;.;

MVP

0.98

MPC

0.0038

ClinPred

0.012

GERP RS

1.5

Varity_R

0.084

gMVP

0.43

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