rs200735475

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2BP4_Strong

The NM_000492.4(CFTR):c.2502T>G(p.Phe834Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,613,160 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F834S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 1 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12B:2

Conservation

PhyloP100: 0.239

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

cystic fibrosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
congenital bilateral absence of vas deferens
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary chronic pancreatitis
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CFTR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.

BP4

Computational evidence support a benign effect (MetaRNN=0.018940032).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.2502T>G	p.Phe834Leu	missense_variant	Exon 15 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.2502T>G	p.Phe834Leu	missense_variant	Exon 15 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00170

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000294

AC:

AN:

251324

AF XY:

0.000331

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000227

AC:

331

AN:

1460858

Hom.:

Cov.:

AF XY:

0.000256

AC XY:

186

AN XY:

726814

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26094

East Asian (EAS)

AF:

0.00

AC:

AN:

39528

South Asian (SAS)

AF:

0.000731

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00105

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5724

European-Non Finnish (NFE)

AF:

0.000183

AC:

203

AN:

1111392

Other (OTH)

AF:

0.000133

AC:

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000171

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41576

American (AMR)

AF:

0.00

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00170

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68020

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.540

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000268

Hom.:

Bravo

AF:

0.0000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000255

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 13, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CFTR c.2502T>G (p.Phe834Leu) variant has been reported in the published literature in individuals with cystic fibrosis (PMID: 33572515 (2021), 28544683 (2017)) and pancreatitis (PMID: 17003641 (2006)). The frequency of this variant in the general population, 0.0013 (32/25102 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. -

Mar 27, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Observed in multiple unrelated individuals with features of cystic fibrosis, pancreatitis, or a positive newborn screen, including some who harbored additional CFTR variants, but segregation information and additional clinical information was not included (Soltysova et al., 2018; Keiles et al., 2006; Bozdogan et al., 2021); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26229102, 25735457, 23248597, 29589582, 29669919, 33572515, 28340353, 20416310, 21521896, 34996830, 28544683, 27311679, GargPK2016[casereport], 17003641) -

Mar 19, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cystic fibrosis

Uncertain:4

Jul 17, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.F834L variant (also known as c.2502T>G and c.2634T>G), located in coding exon 15 of the CFTR gene, results from a T to G substitution at nucleotide position 2502. The phenylalanine at codon 834 is replaced by leucine, an amino acid with highly similar properties. This alteration was first reported in a Caucasian male with recurrent pancreatitis who also carried the 5T variant; however the phase of these alterations is unknown (Keiles S and Kammesheidt A. Pancreas. 2006; 33:221-7). This alteration has also been reported in a cystic fibrosis cohort (Soltysova A et al. Clin Respir J, 2018 Mar;12:1197-1206). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Dec 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 834 of the CFTR protein (p.Phe834Leu). This variant is present in population databases (rs200735475, gnomAD 0.1%). This missense change has been observed in individual(s) with chronic pancreatitis or cystic fibrosis (PMID: 17003641, 21521896). ClinVar contains an entry for this variant (Variation ID: 455769). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) 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. -

Jun 10, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 05, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not specified

Uncertain:2

Aug 29, 2023

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.2502T>G (p.Phe834Leu) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00026 in 396094 control chromosomes in the gnomAD database (v2.1 and v3 genomes dataset), and this frequency is not higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.013). However, the variant was found in the Finnish subpopulation at a frequency of 0.0014, and several studies reported that the incidence of Cystic Fibrosis in Finland is almost tenfold lower than in most other European populations (PMID: 16051530, 2570015, 11813900). These data therefore might suggest a benign role for this variant. The variant, c.2502T>G, has been reported in the literature to be found in cohorts of individuals diagnosed with Cystic Fibrosis (Godoy_2011, Soltysova_2017, Bozdogan_2021), and in patients affected with chronic pancreatitis (Keiles_2006), however without strong evidence of causality. These reports therefore do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 33572515, 21521896, 29589582, 17003641, 20416310, 25735457, 28544683, 29669919, 27311679). Multiple submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Jan 16, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CFTR c.2502T>G; p.Phe834Leu variant (rs200735475) is reported in the literature in the compound heterozygous state in two individuals affected with chronic pancreatitis, and in one individual with cystic fibrosis but no second variant or specific clinical phenotype described (Keiles 2006, Soltysova 2018). This variant is reported as uncertain significance by multiple laboratories in ClinVar (Variation ID: 455769), and is found in the Finnish European population with an allele frequency of 0.13% (32/25,102 alleles) in the Genome Aggregation Database. The phenylalanine at codon 834 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Phe834Leu variant is uncertain at this time. References: Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 33(3):221-7. Soltysova A et al. Comprehensive genetic study of cystic fibrosis in Slovak patients in 25 years of genetic diagnostics. Clin Respir J. 2018 Mar;12(3):1197-1206. -

CFTR-related disorder

Uncertain:2

Aug 07, 2018

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Aug 22, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CFTR c.2502T>G variant is predicted to result in the amino acid substitution p.Phe834Leu. This variant has been reported in combination with another CFTR variant in patients with chronic pancreatitis or cystic fibrosis, although conclusive evidence of pathogenicity was not presented (Keiles et al. 2006. PubMed ID: 17003641; Godoy et al. 2011. PubMed ID: 21521896; Soltysova et al 2017. PubMed ID: 28544683; Bozdogan et al 2021. PubMed ID: 33572515). This variant has also been reported without information on a second potentially causative CFTR variant in two patients with chronic bronchitis or rhinitis (Table S1, Saferali et al. 2022. PubMed ID: 34996830; Godoy et al. 2011. PubMed ID: 21521896). This variant is reported in 0.13% of alleles in individuals of European (Finnish) descent in gnomAD. 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

Benign

0.22

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Uncertain

0.47

T;.;T;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.69

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.72

T;T;T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.019

T;T;T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.60

N;.;.;.

PhyloP100

0.24

PrimateAI

Benign

0.33

PROVEAN

Benign

0.010

N;.;N;.

REVEL

Benign

0.27

Sift

Benign

0.57

T;.;T;.

Sift4G

Benign

1.0

T;.;T;.

Polyphen

0.0

B;.;.;.

Vest4

0.10

MutPred

0.40

Loss of helix (P = 0.1706);.;.;.;

MVP

0.94

MPC

0.0038

ClinPred

0.025

GERP RS

-0.028

Varity_R

0.045

gMVP

0.50

Mutation Taster

=82/18

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over