rs142540482

Positions:

chr7-117509090-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1PM2PM5BP4_Moderate

The NM_000492.4(CFTR):c.221G>A(p.Arg74Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000534 in 1,612,916 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. R74W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00056 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:13B:1

Conservation

PhyloP100: 3.83

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:

CFTR (HGNC:):

CFTR links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a helix (size 27) in uniprot entity CFTR_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117509089-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.20756286).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.221G>A	p.Arg74Gln	missense_variant	3/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.221G>A	p.Arg74Gln	missense_variant	3/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000263

AC:

AN:

250994

Hom.:

AF XY:

0.000236

AC XY:

AN XY:

135664

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000529

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000565

AC:

825

AN:

1460682

Hom.:

Cov.:

AF XY:

0.000550

AC XY:

400

AN XY:

726748

show subpopulations

Gnomad4 AFR exome

AF:

0.0000598

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000376

Gnomad4 NFE exome

AF:

0.000710

Gnomad4 OTH exome

AF:

0.000431

GnomAD4 genome

AF:

0.000243

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000427

Hom.:

Bravo

AF:

0.000280

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00105

AC:

ExAC

AF:

0.000189

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3474

EpiCase

AF:

0.000327

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:13Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:7

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
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, BP2, BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 04, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 74 of the CFTR protein (p.Arg74Gln). This variant is present in population databases (rs142540482, gnomAD 0.05%). This missense change has been observed in individual(s) with chronic pancreatitis (PMID: 17003641, 21520337, 22427236, 25033378). ClinVar contains an entry for this variant (Variation ID: 53456). 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 affects CFTR function (PMID: 31561038). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a 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	Johns Hopkins Genomics, Johns Hopkins University	Feb 13, 2023	Previously reported CFTR variant that has been identified in individuals with pancreatitis and has an entry in ClinVar (Variation ID: 53456). This CFTR variant (rs142540482) is rare (<0.1%) in a large population dataset (gnomADv2.1.1: 72/282380 total alleles; 0.0255%; no homozygotes). Functional studies have shown that this variant has a normal chloride current, but impaired conductance of and permeability to bicarbonate. The latter has been be associated with pancreatitis risk. The clinical significance of this variant is uncertain at this time. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 24, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 04, 2024	The p.R74Q variant (also known as c.221G>A), located in coding exon 3 of the CFTR gene, results from a G to A substitution at nucleotide position 221. The arginine at codon 74 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in an individual with idiopathic chronic pancreatitis who was negative for mutations in the PRSS1 gene (Rosendahl J et al. Pancreatology, 2010 May;10:165-72). Functional studies found that this variant did not affect chloride current density, but significantly reduced bicarbonate permeability and conductance in HEK 293T cells, which may increase the risk of pancreatitis (LaRusch J et al. PLoS Genet., 2014 Jul;10:e1004376; Kim Y et al. Cell Mol Gastroenterol Hepatol, 2020 Sep;9:79-103). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on available evidence, this variant is unlikely to be causative of classic CF, however its clinical contribution to the development of a CFTR-related disorder is uncertain. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 25, 2018	- -

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 19, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 18, 2024	The CFTR c.221G>A (p.Arg74Gln) variant (also known as R74Q) has been reported in the published literature in individuals affected with pancreatitis (PMID: 17003641 (2006), 20460947 (2010), 21520337 (2011), 22427236 (2013), 38871151 (2024)), congenital absence of the vas deferens (PMID: 21520337 (2011), 31845523 (2020)), and severe sepsis (PMID: 34973142 (2022)). Published functional studies observed the variant to have chloride conductance comparable to the wild-type (PMID: 25033378 (2014)) or moderately reduced (46%), though improved (127%) with ELX/TEZ/IVA treatment (PMID: 38388235 (2024)). Reduced bicarbonate permeability and conductance was observed with this variant (PMID: 25033378 (2014), 31561038 (2020)). Consequently, this may support an association of the variant to pancreatitis, though inconclusive (PMID: 25033378 (2014), 36264955 (2022)). The frequency of this variant in the general population, 0.00083 (42/50662 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 07, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 26, 2022	The CFTR c.221G>A; p.Arg74Gln variant (rs142540482) has been reported in multiple pancreatitis patients (Keiles 2006, Masson 2013, Rosendahl 2013, LaRusch 2014) but did not show significant enrichment in patients compared to unaffected individuals (Rosendahl 2013, LaRusch 2014). Functional studies indicate that the variant protein has a defect in bicarbonate transport, but has no impact on chloride transport activity (LaRusch 2014). This variant is reported in ClinVar (Variation ID: 53456) and is found in the non-Finnish European population with an overall allele frequency of 0.05% (64/128878 alleles) in the Genome Aggregation Database. The arginine at residue 74 is moderately conserved, and computational algorithms are uncertain whether this variant is neutral or deleterious (REVEL: 0.483). Due to the limited and conflicting information regarding this variant, its clinical significance cannot be determined with certainty. References: Keiles S et al. Identification of CFTR, PRSS1, and SPINK1 mutations in 381 patients with pancreatitis. Pancreas. 2006 33(3):221-7. PMID: 17003641 LaRusch J et al. Mechanisms of CFTR functional variants that impair regulated bicarbonate permeation and increase risk for pancreatitis but not for cystic fibrosis. PLoS Genet. 2014 10(7):e1004376. PMID: 25033378. 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. Rosendahl J et al. CFTR, SPINK1, CTRC and PRSS1 variants in chronic pancreatitis: is the role of mutated CFTR overestimated? 2013 Gut. 62(4):582-92. PMID: 22427236. -

CFTR-related disorder

Uncertain:1Benign: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. -
Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 14, 2024	The CFTR c.221G>A variant is predicted to result in the amino acid substitution p.Arg74Gln. This variant was reported in an individual with Cystic fibrosis (Schrijver et al 2005. PubMed ID: 16049310; LaRusch J et al 2014. PubMed ID: 25033378; Tabor HK et al 2014. PubMed ID: 25087612). This variant is reported in 0.050% of alleles in individuals of European (Non-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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Apr 27, 2023

Variant summary: CFTR c.221G>A (p.Arg74Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. One publication (Ramalho_2015) and 2/4 computational tools predict that the variant creates a cryptic 3' acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00026 in 254510 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Chronic Pancreatitis Risk (0.00026 vs 0.0063), allowing no conclusion about variant significance. The variant was reported in one patient with a CFTR-related disorder (unspecified phenotype) however, this patient also carried a pathogenic CFTR variant (c.3846G>A, p.W1282X) in cis, supporting a benign role for the variant of interest in this case (Trujillano_2013). On the other hand, multiple publications cite the variant in individuals with pancreatitis (e.g. Keiles_2006, Steiner_2011, Rosendahl_2012, Masson_2013, LaRusch_2014). In several patients, the variant was reported along with p.R297Q (phase not specified), and this co-occurring variant (i.e. c.890G>A, p.Arg297Gln), was also reported in several patients with idiopathic pancreatitis. Additionally, the variant was found to be associated with pancreatitis in a case control study when patients also have the SPINK1 pathogenic mutation p.N34S (LaRusch_2014). This study also reported experimental evidence that the c.221G>A, p.Arg74Gln variant results in significantly reduced bicarbonate channel function (LaRusch_2014). Similarly, another functional study has reported that the variant impairs the association of CFTR with WNK1, reducing WNK1-mediated regulation of HCO3- channel activity (Kim_2019). Authors of the former study (LaRusch_2014) concluded that variants that impair bicarbonate permeation may increase the risk for pancreatitis, but not for cystic fibrosis. In contrast, a recent meta-analysis of CFTR variants characterized by a selective bicarbonate conductance defect did not find a significant association of p.Arg74Gln with chronic pancreatitis (Berke_2022). The following publications have been ascertained in the context of this evaluation (PMID: 36264955, 17003641, 34973142, 31561038, 25033378, 23951356, 29859674, 34782259, 22427236, 21520337, 23687349). Eleven submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classfied the variant as either VUS (n=10) or likely benign (n=1). Based on the evidence outlined above, the variant was classified as VUS. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Uncertain

0.13

BayesDel_noAF

Pathogenic

0.29

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

T;.;.;T;.

Eigen

Benign

0.033

Eigen_PC

Uncertain

0.22

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.92

D;D;D;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.21

T;T;T;T;T

MetaSVM

Uncertain

-0.11

MutationAssessor

Uncertain

2.2

M;.;.;.;M

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.58

N;.;.;N;.

REVEL

Uncertain

0.48

Sift

Benign

0.41

T;.;.;T;.

Sift4G

Benign

0.13

T;.;.;T;.

Polyphen

0.0030

B;.;.;.;.

Vest4

0.74

MVP

0.95

MPC

0.0038

ClinPred

0.049

GERP RS

5.7

Varity_R

0.41

gMVP

0.88

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