7-117590357-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4BP6

The NM_000492.4(CFTR):c.1684G>A(p.Val562Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000168 in 1,602,534 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 0.00020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:9B:5

Conservation

PhyloP100: 7.38

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 2 ACMG points.

PM1

In a domain ABC transporter 1 (size 223) in uniprot entity CFTR_HUMAN there are 54 pathogenic changes around while only 9 benign (86%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.31232405).

BP6

Variant 7-117590357-G-A is Benign according to our data. Variant chr7-117590357-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35830.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=8}. Variant chr7-117590357-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.1684G>A	p.Val562Ile	missense_variant	Exon 13 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.1684G>A	p.Val562Ile	missense_variant	Exon 13 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000191

AC:

AN:

152014

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000140

AC:

AN:

250340

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

135422

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000165

AC:

239

AN:

1450402

Hom.:

Cov.:

AF XY:

0.000166

AC XY:

120

AN XY:

721284

show subpopulations

Gnomad4 AFR exome

AF:

0.000211

Gnomad4 AMR exome

AF:

0.000383

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000165

Gnomad4 OTH exome

AF:

0.000436

GnomAD4 genome

AF:

0.000197

AC:

AN:

152132

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.000287

ExAC

AF:

0.000157

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.000600

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:9Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:4Benign:3

Jul 22, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 562 of the CFTR protein (p.Val562Ile). This variant is present in population databases (rs1800097, gnomAD 0.03%). This missense change has been observed in individual(s) with CFTR-related disorders including congenital absence of the vas deferens, oligospermia, chronic pancreatitis, and cystic fibrosis (PMID: 1379210, 9239681, 16189704, 17329263, 17331079, 19810821, 20021716, 20691141, 21520337, 23951356, 25667564, 25910067). This variant is also known as 1816G>A. ClinVar contains an entry for this variant (Variation ID: 35830). 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%. Experimental studies have shown that this missense change does not substantially affect CFTR function (PMID: 17098864, 21708286). 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. -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

This variant is interpreted as a Uncertain Significance - Conflicting Evidence, for Cystic fibrosis, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:17098864). BP2 => Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern (PMID:17329263). -

Jun 08, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Dec 20, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 19, 2025

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant NM_000492.4(CFTR):c.1684G>A (p.Val562Ile) is found frequent in Mendelics internal database. GnomAD frequency 0.0001679 with no Homozygotes. In Silico Predictors: Benign -

not provided

Uncertain:2Benign:1

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 31, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 09, 2017

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

CFTR-related disorder

Uncertain:2

Nov 30, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CFTR c.1684G>A variant is predicted to result in the amino acid substitution p.Val562Ile. This variant was reported in a Moroccan patient with cystic fibrosis (Telleria et al. 1999. PubMed ID: 10447267). However, there was no further evidence that the p.Val562Ile variant was actually causative in this case. A later study reported cellular and genetic evidence that the p.Val562Ile variant may be benign (Roxo-Rosa et al. 2006. PubMed ID: 17098864). This variant is reported in 0.031% of alleles in individuals of Latino descent in gnomAD. In ClinVar, this variant has conflicting interpretations ranging from uncertain to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/35830/). While we suspect this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Uncertain:1

May 07, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not specified

Benign:1

Feb 06, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: CFTR c.1684G>A (p.Val562Ile) results in a conservative amino acid change located in the ABC transporter-like domain (IPR003439) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. However, a recently developed integrative tool for in-silico analysis of missense variants in the CFTR gene (CYSMA), reporting a sensitivity of 89% and a specificity of 85% classified this variant as a True Negative (Sasorith_2020). This tool generates a set of computationally derived data, ranging from evolutionary conservation to functional observations from threedimensional structures, provides all available allelic frequencies, clinical observations, and references for functional studies. The variant allele was found at a frequency of 0.00014 in 250586 control chromosomes (gnomAD and publications). This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00014 vs 0.013), allowing no conclusion about variant significance. c.1684G>A, has been reported in the literature in individuals affected with a wide spectrum of phenotypes ranging from asymptomatic to CF, CBAVD, infertility, diffuse bronchiectasis and idiopathic chronic pancreatitis, many of whom were not uniformly analyzed and had non-informative genotypes (Braekeleer_1996, Peuchal_1999, Telleria_1999, Grangeia_2004, Cohn_2005, Claustres_2017, Lucarelli_2017). These data do not allow any conclusion about variant significance. In addition, several publications have reported this variant in cis as c.[1210-34_1210-6TG[11]T[5];1684G>A] (TG11T5, T5, A1006E) in combination with another pathogenic variant in trans that could have explained some of the symptoms reported (McGinniss_2005, Alonso_2007, Ratbi_2007, Lucarelli_2015, Sofia_2018). Of note, at-least one patient homozygous for 2347delG with this variant in cis on both his alleles has been reported in an unpublished study (Giordan et al) (cited by Ratbi_2007). Similarly, at-least 2 unaffected patients with this variant and p.F508del in trans have been reported as a personal communication with C. Barreto (cited by Roxo-Rosa_2006). Recently, this variant genotype (c.[1210-34_1210-6TG[11]T[5];1684G>A]) was reported with a hemizygous causative highly penetrant truncation variant in the X-linked ADGRG2 gene (c.251C>G, p.Ser84*) in a patient with CBAVD, bilateral epididymis enlargement, azoospermia and hypovolemia (Pagin_2020). The authors concluded that the presence of the CFTR variant in this patient may be incidental and that the loss of function variant in ADGRG2 is sufficient to produce the CAVD phenotype. These reports provide additional supporting evidence that the variant of interest was not causative of disease in these patients. Three independent functional studies report no effects on either of CFTR trafficking, the maturation process, channel activity or mRNA expression levels (Roxo-Rosa_2006, Fresquet_2011, Raraigh_2018). The CFTR2 database reports this variant as not causative of CF when combined with another CF-causing variant. The following publications have been ascertained in the context of this evaluation (PMID: 17331079, 9239681, 10923036, 28603918, 15758663, 1379210, 21708286, 18716917, 15333598, 17572159, 28736296, 25910067, 16189704, 31845523, 20651897, 10445602, 29805046, 17329263, 17098864, 31674704, 30134826, 10447267, 20691141, 19812525). ClinVar contains an entry for this variant (Variation ID: 35830). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Uncertain

0.12

BayesDel_noAF

Pathogenic

0.24

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.57

D;.;T;.

Eigen

Benign

-0.047

Eigen_PC

Benign

0.15

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.31

T;T;T;T

MetaSVM

Uncertain

0.025

MutationAssessor

Benign

-0.15

N;.;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Benign

-0.64

N;.;N;.

REVEL

Uncertain

0.64

Sift

Benign

0.042

D;.;D;.

Sift4G

Benign

0.071

T;.;T;.

Polyphen

0.0080

B;.;.;.

Vest4

0.81

MVP

0.99

MPC

0.0045

ClinPred

0.084

GERP RS

3.9

Varity_R

0.45

gMVP

0.84

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