NM_000492.4:c.221G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1PM5PP2BP4_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 Uncertain significance.

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

Publications

18 publications found

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 Gene-Disease associations (from GenCC):

cystic fibrosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
congenital bilateral absence of vas deferens
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary chronic pancreatitis
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CFTR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 26 uncertain in NM_000492.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-117509090-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1706004.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.221G>A	p.Arg74Gln	missense_variant	Exon 3 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.221G>A	p.Arg74Gln	missense_variant	Exon 3 of 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

GnomAD2 exomes

AF:

0.000263

AC:

AN:

250994

AF XY:

0.000236

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 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

African (AFR)

AF:

0.0000598

AC:

AN:

33450

American (AMR)

AF:

0.0000447

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39660

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86226

European-Finnish (FIN)

AF:

0.0000376

AC:

AN:

53150

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000710

AC:

789

AN:

1111254

Other (OTH)

AF:

0.000431

AC:

AN:

60336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

107

143

179

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000243

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74418

show subpopulations

African (AFR)

AF:

0.0000963

AC:

AN:

41558

American (AMR)

AF:

0.0000654

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000456

AC:

AN:

68000

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000423

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

Feb 13, 2023

Johns Hopkins Genomics, Johns Hopkins University

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 05, 2022

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

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 -

May 25, 2018

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Oct 04, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 22, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Oct 24, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

not provided

Uncertain:4

Nov 18, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 31, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, Kim 2020). This variant is reported in ClinVar (Variation ID: 53456) and is found in the non-Finnish European population with an allele frequency of 0.05% (64/128878 alleles) in the Genome Aggregation Database (v2.1.1). 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: Kim Y et al. Regulation of CFTR Bicarbonate Channel Activity by WNK1: Implications for Pancreatitis and CFTR-Related Disorders. Cell Mol Gastroenterol Hepatol. 2020;9(1):79-103. PMID: 31561038. 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. -

Jul 19, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 07, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CFTR-related disorder

Uncertain:1Benign:1

Jun 14, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

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. 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. -

not specified

Uncertain:1

Apr 27, 2023

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

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

3.8

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

Mutation Taster

=11/89

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over