rs143486492

chr7-117540120-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_000492.4(CFTR):c.890G>A(p.Arg297Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000885 in 1,613,130 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. R297W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (0 hom.)
• Consequence: CFTR NM_000492.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10 B:8
• Conservation: PhyloP100: 6.39

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 1 ACMG points.

• PM1: In a domain ABC transmembrane type-1 1 (size 284) in uniprot entity CFTR_HUMAN there are 173 pathogenic changes around while only 18 benign (91%) in NM_000492.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19872731).
• BP6: Variant 7-117540120-G-A is Benign according to our data. Variant chr7-117540120-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 54082.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=7, Uncertain_significance=9, Benign=1}. Variant chr7-117540120-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4	c.890G>A	p.Arg297Gln	missense_variant	8/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11	c.890G>A	p.Arg297Gln	missense_variant	8/27	1	NM_000492.4	P2

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152058 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00173

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00119

Gnomad OTH AF: 0.000959

GnomAD3 exomes AF: 0.000567 AC: 142 AN: 250572 Hom.: 0 AF XY: 0.000554 AC XY: 75 AN XY: 135496

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00107

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000907 AC: 1325 AN: 1460952 Hom.: 0 Cov.: 30 AF XY: 0.000876 AC XY: 637 AN XY: 726824

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.000358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.00112

Gnomad4 OTH exome AF: 0.000795

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152178 Hom.: 0 Cov.: 32 AF XY: 0.000618 AC XY: 46 AN XY: 74394

Gnomad4 AFR AF: 0.000169

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00119

Gnomad4 OTH AF: 0.000949

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.000552

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00163 AC: 14

ExAC AF: 0.000486 AC: 59

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.000873

EpiControl AF: 0.000889

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cystic fibrosis Uncertain:4 Benign:4

Uncertain significance, criteria provided, single submitter	curation	Institute of Human Genetics, University of Leipzig Medical Center	Sep 05, 2022	This variant was identified in 1 patient with a clinically confirmed diagnosis of cystic fibrosis. The variant was classified in the context of a project re-classifying variants in the German Cystic Fibrosis Registry (Muko.e.V.). Link: https://www.muko.info/angebote/qualitaetsmanagement/register/cf-einrichtungen/mukoweb. Criteria applied: PS3_SUP, PM3, PM5, BS3, BS4, BP2 -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jun 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 09, 2019	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	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Mar 30, 2022	- -

not provided Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 13, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 26, 2022	The CFTR c.890G>A; p.Arg297Gln variant (rs143486492) is reported in the literature in multiple individuals affected with CFTR-related disorders (Casals 2004, Gallati 2009, Keiles 2006, Masson 2013, Sultan 2012). However, this variant has also been reported on the same chromosome as the 5T variant (Hughes 2001, Tzetis 2001), and did not segregate with disease in at least one family (Dorval 1995). This variant is reported in ClinVar (Variation ID: 54082), and is found in the non-Finnish European population with an allele frequency of 0.12% (153/128492 alleles) in the Genome Aggregation Database. The arginine at codon 297 is highly conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.717). Functional analyses of the variant protein show normal chloride channel activity (Chen 2000, Seibert 1997), but a defect in bicarbonate transport (Choi 2001). Due to conflicting information, the clinical significance of the p.Arg297Gln variant is uncertain at this time. References: Casals T et al. Different CFTR mutational spectrum in alcoholic and idiopathic chronic pancreatitis? Pancreas. 2004 28(4):374-9. PMID: 15097853. Chen EY et al. Cystic fibrosis transmembrane conductance regulator has an altered structure when its maturation is inhibited. Biochemistry. 2000 Apr 4;39(13):3797-803. PMID: 10736180. Choi JY et al. Aberrant CFTR-dependent HCO3- transport in mutations associated with cystic fibrosis. Nature. 2001 Mar 1;410(6824):94-7. PMID: 11242048. Dorval I et al. French CF family genotype analysis shows that the R297Q mutation is a rare polymorphism. Hum Mutat. 1995;6(4):334-5. PMID: 8680407. Gallati S et al. Cystic fibrosis transmembrane conductance regulator mutations in azoospermic and oligospermic men and their partners. Reprod Biomed Online. 2009 19(5):685-94. PMID: 20021716. Hughes D et al. Mutation and haplotype analysis of the CFTR gene in atypically mild cystic fibrosis patients from Northern Ireland. J Med Genet. 2001 Feb;38(2):136-9. PMID: 11288718. Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 33(3):221-7. PMID: 17003641. Masson E et al. A conservative assessment of the major genetic causes of idiopathic chronic pancreatitis: data from a comprehensive analysis of PRSS1, SPINK1, CTRC and CFTR genes in 253 young French patients. PLoS One. 2013 8(8):e73522. PMID: 23951356. Seibert FS et al. Disease-associated mutations in cytoplasmic loops 1 and 2 of cystic fibrosis transmembrane conductance regulator impede processing or opening of the channel. Biochemistry. 1997 Sep 30;36(39):11966-74. PMID: 9305991. Sultan M et al. Genetic prevalence and characteristics in children with recurrent pancreatitis. J Pediatr Gastroenterol Nutr. 2012 54(5):645-50. PMID: 22094894. Tzetis M et al. CFTR gene mutations--including three novel nucleotide substitutions--and haplotype background in patients with asthma, disseminated bronchiectasis and chronic obstructive pulmonary disease. Hum Genet. 2001 108(3):216-21. PMID: 11354633. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 08, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 21, 2023	The CFTR c.890G>A (p.Arg297Gln) variant has been reported in the published literature in individuals with mild/atypical CF, occurring in cis with the 5T allele (PMID: 11288718 (2001)). The variant has been reported in individuals with pancreatitis (PMID: 22094894 (2012), 28502372 (2017), 23951356 (2003), 17003641 (2006), 25033378 (2014)) and other CFTR-related disorders (PMID: 33946859 (2021)) as well as in healthy individuals who carried a CF-causing mutation on the opposing chromosome (PMID: 29589582 (2018), 8680407 (1995), 17489851 (2007)). Functional studies indicate this variant has a neutral effect on CFTR protein processing and chloride channel activity, but significantly reduced bicarbonate transport (PMID: 11242048 (2001), 9305991 (1997)). The frequency of this variant in the general population, 0.005 (24/4832 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 conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2019	Observed in individuals with pancreatitis (Casals 2004, Keiles 2006, Suttton 2010, Sultan 2012); Observed in individuals with cystic fibrosis and/or an abnormal newborn screen (Scotet 2000, Hughes 2001, Scotet 2001, Abou Alaiwa 2014); Published functional studies are inconclusive: reduced bicarbonate:chloride transport ratio with chloride channel function similar to wildtype (Seibert 1997, Choi 2001); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 11788091, 15097853, 7551394, 9305991, 11242048, 11022925, 11288718, 11168024, 24418186, 17003641, 22094894, 20846557, 1284534, 23523379, 20416310, 29589582, 11354633, 23951356, 8818956, 16778595, 8680407, 23514810, 20021716, 25087612, 18456578, 11288708) -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 26, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 02, 2017	p.Arg297Gln variant in exon 8 of CFTR: This variant is not expected to have clin ical significance because it has been identified in 2 unaffected individuals in trans with a pathogenic variant (Dorval 1995). This variant has also been report ed in ClinVar (Variation ID 54082) and has been identified in 0.1% (155/126020) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnoma d.broadinstitute.org; dbSNP rs143486492). Computational prediction tools and con servation analysis suggest that the p.Arg297Gln variant may not impact the prote in, though this information is not predictive enough to rule out pathogenicity. ACMG/AMP Criteria applied: BS2, BP4. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 13, 2023	Variant summary: CFTR c.890G>A (p.Arg297Gln) results in a conservative amino acid change located in the in the first transmembrane domain (IPR011527) and within the second cytoplasmic loop (Choi 2001) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00056 in 251720 control chromosomes (gnomAD, publications), predominantly at a frequency of 0.0011 within the Non-Finnish European subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00056 vs 0.013), allowing no conclusion about variant significance. c.890G>A has been reported in the literature in multiple individuals affected with a milder, atypical form of cystic fibrosis (Graham 1991,Hughes 2001) and was detected during newborn screening in neonates with positive sweat test results (Scotet 2000, Bozdogan_2021), however in Scotet_2000 the CFTR gene was not fully sequenced. The variant was also reported with various CFTR-related phenotypes, e.g. asthma (Tzetis 2001) infertility (Ravnik-Glavac 2001, Gallati 2009), and cholestasis (Wang_2020). However, multiple affected individuals were reported to carry another pathogenic CFTR variant (5T) in cis with the variant of interest (Graham 1991, Hughes 2001, Tzetis 2001), along with a family study indicating that the variant did not segregate with the disease (Dorval 1995). The variant was also reported in patients affected with chronic or recurrent pancreatitis (e.g. Casals 2004, Keiles 2006, Sutton 2010, Sultan 2012, Masson 2013, LaRusch_2014). However, some of these patients also carried the variant CFTR c.221G>A (p.Arg74Gln) (Keiles 2006, Masson 2013), and this co-occurring variant is internally classified as a VUS-possibly pathogenic variant for Chronic Pancreatitis Risk. Therefore, these data do not allow clear conclusions about variant significance. A functional study found the variant to be comparable to the wild type in maturation and chloride channel function (Seibert 1997), while another study reported a significantly reduced bicarbonate transport (Choi 2001). According to a later study, other variants that impair bicarbonate permeation may increase the risk for pancreatitis, but not for cystic fibrosis (LaRusch 2014). Sixteen clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as VUS (n=10) and likely benign/benign (n=6). Based on the evidence outlined above, the variant was classified as likely benign. -

CFTR-related disorder Benign:1

Likely benign, 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. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Uncertain	0.081	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;.;D;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.20	T;T;T;T;T
MetaSVM	Uncertain	0.35	D
MutationAssessor	Uncertain	2.1	M;.;.;.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N;.;.;N;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.025	D;.;.;D;.
Sift4G	Uncertain	0.038	D;.;.;D;.
Polyphen		0.13	B;.;.;.;.
Vest4		0.83
MVP		0.98
MPC		0.0044
ClinPred		0.037	T
GERP RS		5.4
Varity_R		0.72
gMVP		0.89

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: rs143486492; hg19: chr7-117180174; COSMIC: COSV99133519;