rs1800097

chr7-117590357-G-Achr7-117590357-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4 BP6

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V562A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:4
• Conservation: PhyloP100: 7.38

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain 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=4, Uncertain_significance=10}. Variant chr7-117590357-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.1684G>A	p.Val562Ile	missense_variant	13/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.1684G>A	p.Val562Ile	missense_variant	13/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152014 Hom.: 0 Cov.: 32

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: 35 AN: 250340 Hom.: 0 AF XY: 0.000126 AC XY: 17 AN XY: 135422

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.: 0 Cov.: 30 AF XY: 0.000166 AC XY: 120 AN XY: 721284

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: 30 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74384

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.: 0

Bravo AF: 0.000287

ExAC AF: 0.000157 AC: 19

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000600

EpiControl AF: 0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:5 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Apr 04, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Nov 02, 2022	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). 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. Experimental studies have shown that this missense change does not substantially affect CFTR function (PMID: 17098864, 21708286). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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	Genome-Nilou Lab	Jul 22, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Dec 20, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 08, 2022	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. -
Uncertain significance, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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). -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -

not provided Uncertain:2 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 09, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 21, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 31, 2022	- -

CFTR-related disorder Uncertain:2

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. -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Nov 30, 2023	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. -

Hereditary pancreatitis Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

May 07, 2021

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Feb 06, 2024

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	D
BayesDel_noAF	Pathogenic	0.24
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D;.;T;.
Eigen	Benign	-0.047
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Benign	0.31	T;T;T;T
MetaSVM	Uncertain	0.025	D
MutationAssessor	Benign	-0.15	N;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
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	T
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

Other links and lift over

dbSNP: rs1800097; hg19: chr7-117230411;