rs200735475

Positions:

chr7-117594941-T-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2502T>G	p.Phe834Leu	missense_variant	15/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.2502T>G	p.Phe834Leu	missense_variant	15/27	1	NM_000492.4	ENSP00000003084	P2	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

GnomAD3 exomes

AF:

0.000294

AC:

AN:

251324

Hom.:

AF XY:

0.000331

AC XY:

AN XY:

135840

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 SAS exome

AF:

0.000849

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

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000731

Gnomad4 FIN exome

AF:

0.00105

Gnomad4 NFE exome

AF:

0.000183

Gnomad4 OTH exome

AF:

0.000133

GnomAD4 genome

AF:

0.000171

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000255

AC XY:

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00170

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000229

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

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 27, 2023	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) -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 19, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 30, 2020	- -

Cystic fibrosis

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Apr 27, 2022	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 phase (cis/trans) 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. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 28, 2022	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). 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	Counsyl	Jan 05, 2018	- -

not specified

Uncertain:2

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.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. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 16, 2019	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

Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 22, 2024	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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 07, 2018	- -

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

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;.;.;.

MutationTaster

Benign

0.98

N;N

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

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