rs150157202

Positions:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_000492.4(CFTR):c.2260G>A(p.Val754Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,612,184 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 6 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:14

Conservation

PhyloP100: -0.290

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 -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008483261).

BP6

Variant 7-117592427-G-A is Benign according to our data. Variant chr7-117592427-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53465.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=6, Uncertain_significance=4}. Variant chr7-117592427-G-A is described in Lovd as [Benign]. Variant chr7-117592427-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 6 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2260G>A	p.Val754Met	missense_variant	14/27	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.2260G>A	p.Val754Met	missense_variant	14/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.00171

AC:

260

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00301

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00231

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00182

AC:

453

AN:

248828

Hom.:

AF XY:

0.00193

AC XY:

259

AN XY:

134454

show subpopulations

Gnomad AFR exome

AF:

0.000247

Gnomad AMR exome

AF:

0.00227

Gnomad ASJ exome

AF:

0.000204

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00103

Gnomad FIN exome

AF:

0.00261

Gnomad NFE exome

AF:

0.00244

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.00193

AC:

2814

AN:

1459914

Hom.:

Cov.:

AF XY:

0.00193

AC XY:

1402

AN XY:

726182

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00191

Gnomad4 ASJ exome

AF:

0.000347

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00128

Gnomad4 FIN exome

AF:

0.00317

Gnomad4 NFE exome

AF:

0.00211

Gnomad4 OTH exome

AF:

0.00134

GnomAD4 genome

AF:

0.00171

AC:

260

AN:

152270

Hom.:

Cov.:

AF XY:

0.00168

AC XY:

125

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.000481

Gnomad4 AMR

AF:

0.00262

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00124

Gnomad4 FIN

AF:

0.00301

Gnomad4 NFE

AF:

0.00231

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00189

Hom.:

Bravo

AF:

0.00172

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00244

AC:

ExAC

AF:

0.00189

AC:

229

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:6

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 16, 2016	Variant Summary: The c.2260G>A (p.Val754Met) in CFTR gene is a missense change that involves a non- conserved nucleotide and 4/5 in silico tools predict benign outcome. The variant was found in the large and broad cohorts of ExAC project at an allele frequency of 0.0019 (233/117214 chrs tested, including 1 homozygous occurrence). This frequency does not exceed the maximal expected allele frequency of a disease causing CFTR allele (0.013). Several CF patients, who have been found to be carriers of the variant of interest also carried known pathogenic variants in cis and in trans. In addition variant was seen in apparently healthy individuals with severe mutation on the other chromosomes (Sosnay , 2013). In vivo/vitro functional studies showed that the Cl- conductance of CFTR channels formed by V754M CFTR protein is not impaired suggesting that the variant does not affect Cl- channel function of CFTR (Sosnay, 2013). In conclusion, while a mild detrimental effect p.Val754Met resulting in CF spectrum diseases could not be definitely ruled out, there are strong lines of evidence against a severe deleterious effect and its association with CF. Lastly, CFTR2.org classify variant as NON-disease causing. Taking together, by applying ACMG guidelines the variant was classified as Benign. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 22, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 20, 2023	In the published literature, this variant has been observed in unaffected individuals who also carry a CF-causing mutation on the other chromosome, indicating that this variant is not associated with classic CF (PMID: 23276700 (2013), 25824995 (2015)). However, individuals with this variant in combination with a CF-causing mutation on the other chromosome may develop mild symptoms in select organ systems and/or be diagnosed as having a CFTR-related disorder (PMIDs: 10376575 (1999), 17413420 (2007), 15987793 (2005), 17003641 (2006), 16786510 (2006), and 25797027 (2015)). In addition, in vitro functional studies indicate that this variant does not prevent chloride conduction by the CFTR protein (PMID: 25797027 (2015) and 23974870 (2013)), but it may reduce the level of mature CFTR protein (PMID: 25797027 (2015)). The frequency of this variant in the general population, 0.004 (94/26044 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 10, 2023	The CFTR c.2260G>A; p.Val754Met variant (rs150157202) has been reported in patients diagnosed with cystic fibrosis (Loumi 2008, Orozco 2000), but was found to be in-cis with truncating variants (Lucarelli 2015, Niel 2006). The variant has also been found in individuals without clinical symptoms of cystic fibrosis, in-trans with other pathogenic variants (Krenkova 2013, Niel 2006, Sosnay 2013), and thus is considered non-CF causing (CFTR2 database). Functional characterization of the variant protein also indicates no defects in protein maturation or chloride transport activity (Sosnay 2013). However, the variant has been reported in multiple individuals with chronic pancreatitis (Niel 2006, Keiles 2006) and oligospermy (Gallati 2009), and thus its role in CFTR-related disorders is uncertain. The p.Val754Met variant is listed in ClinVar (Variation ID: 53465) and is observed in the general population at a frequency of 0.18% (509/280,228 alleles, including 2 homozygotes) in the Genome Aggregation Database. The valine at residue 754 is weakly conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.518). Although the p.Val754Met variant is not associated with classic cystic fibrosis, its clinical significance for CFTR-related disorders is uncertain. References: CFTR2 database: http://cftr2.org/ Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 Nov;19(5):685-94. PMID: 20021716. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 Oct;33(3):221-7. PMID: 17003641. Krenkova P et al. Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. J Cyst Fibros. 2013 Sep;12(5):532-7. PMID: 23276700. Loumi O et al. CFTR mutations in the Algerian population. J Cyst Fibros. 2008 Jan;7(1):54-9. PMID: 17572159. Lucarelli M et al. A Genotypic-Oriented View of CFTR Genetics Highlights Specific Mutational Patterns Underlying Clinical Macrocategories of Cystic Fibrosis. Mol Med. 2015 Apr 21;21:257-75. PMID: 25910067. Niel F et al. A new large CFTR rearrangement illustrates the importance of searching for complex alleles. Hum Mutat. 2006 Jul;27(7):716-7. PMID: 16786510 Orozco L et al. Spectrum of CFTR mutations in Mexican cystic fibrosis patients: identification of five novel mutations (W1098C, 846delT, P750L, 4160insGGGG and 297-1G-->A). Hum Genet. 2000 Mar;106(3):360-5. PMID: 10798368 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Cystic fibrosis

Uncertain:1Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Mar 09, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 04, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Aug 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Aug 09, 2019	- -
Benign, criteria provided, single submitter	curation	CFTR-France	Mar 26, 2018	the variant does not result in CFTR-RD neither -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Mar 13, 2024	- -

CFTR-related disorder

Uncertain:1

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. -

Hereditary pancreatitis

Benign:1

Likely benign, criteria provided, single submitter

curation

Sema4, Sema4

Oct 12, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

0.17

DANN

Benign

0.15

DEOGEN2

Uncertain

0.49

T;.;T;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.75

T;T;T;T

M_CAP

Benign

0.070

MetaRNN

Benign

0.0085

T;T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

-0.055

N;.;.;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

0.40

N;.;N;.

REVEL

Uncertain

0.52

Sift

Benign

0.56

T;.;T;.

Sift4G

Benign

0.95

T;.;T;.

Polyphen

0.014

B;.;.;.

Vest4

0.14

MVP

0.88

MPC

0.0041

ClinPred

0.00060

GERP RS

-4.6

Varity_R

0.17

gMVP

0.16

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