7-117592541-C-G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_000492.4(CFTR):c.2374C>G(p.Arg792Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 1,521,040 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R792L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:13

Conservation

PhyloP100: 0.616

Publications

27 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 1 ACMG points.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.2374C>G	p.Arg792Gly	missense_variant	Exon 14 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.2374C>G	p.Arg792Gly	missense_variant	Exon 14 of 27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000127

AC:

AN:

181308

AF XY:

0.000157

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000945

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000226

Gnomad OTH exome

AF:

0.000241

GnomAD4 exome

AF:

0.0000241

AC:

AN:

1368778

Hom.:

Cov.:

AF XY:

0.0000268

AC XY:

AN XY:

671288

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30404

American (AMR)

AF:

0.000944

AC:

AN:

29666

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20236

East Asian (EAS)

AF:

0.00

AC:

AN:

38882

South Asian (SAS)

AF:

0.00

AC:

AN:

69010

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49966

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5312

European-Non Finnish (NFE)

AF:

0.00000281

AC:

AN:

1068940

Other (OTH)

AF:

0.0000355

AC:

AN:

56362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41532

American (AMR)

AF:

0.000457

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68032

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

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:

0.00

Hom.:

Bravo

AF:

0.0000642

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000994

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:4

Oct 31, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.R792G variant (also known as c.2374C>G), located in coding exon 14 of the CFTR gene, results from a C to G substitution at nucleotide position 2374. The arginine at codon 792 is replaced by glycine, an amino acid with dissimilar properties. In a study of 42 men with congenital bilateral absence of the vas deferens, this variant was detected in one individual with another missense variant, p.R766M, on the other allele (Ravnik-Glavac M et al. Hum. Hered.;50:318-9). In vitro studies demonstrated that the variant significantly reduces chloride current and open probabilities of the channel, but still retains approximately 50% of channel activity (Vankeerberghen A et al. Hum. Mol. Genet., 1998 Oct;7:1761-9). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Sep 05, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 05, 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 glycine, which is neutral and non-polar, at codon 792 of the CFTR protein (p.Arg792Gly). This variant is present in population databases (rs145449046, gnomAD 0.09%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 9736778). ClinVar contains an entry for this variant (Variation ID: 35840). 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: 9736778). 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. -

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Uncertain:4

Breakthrough Genomics, Breakthrough Genomics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 12, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 16, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM2 -

Aug 22, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29216686, 20932301, 9736778, 12940920, 26277102, 10878476) -

not specified

Uncertain:2

May 10, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CFTR c.2374C>G; p.Arg792Gly variant (rs145449046) has been described in the compound heterozygous state in one individual with congenital bilateral absence of the vas deferens (Ravnik-Glavac 2000). It is reported as a variant of uncertain significance in ClinVar (Variation ID: 35840) and observed in the Latino population at an overall frequency of 0.095% (21/22002 alleles) in the Genome Aggregation Database. The arginine at codon 792 is highly conserved, and computational algorithms (SIFT, PolyPhen-2) predict that this variant is deleterious. In vitro functional studies of the variant protein demonstrate reduced chloride current and disruption of a consensus recognition site used for CFTR activation (Vankeerberghen 1998). However, due to limited clinical information regarding this variant, its clinical significance cannot be determined with certainty. References: Ravnik-Glavac M et al. Two novel missense mutations (R766M and R792G) in exon 13 of the CFTR gene in a patient with congenital bilateral absence of the vas deferens. Hum Hered. 2000 Sep-Oct;50(5):318-9. Vankeerberghen A et al. Characterization of 19 disease-associated missense mutations in the regulatory domain of the cystic fibrosis transmembrane conductance regulator. Hum Mol Genet. 1998 Oct;7(11):1761-9. -

Jun 11, 2025

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.2374C>G (p.Arg792Gly) results in a non-conservative amino acid change located in the CFTR regulator domain (IPR025837) of the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.00013 in 181538 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Congenital Bilateral Absence Of The Vas Deferens (0.00013 vs 0.013), allowing no conclusion about variant significance. c.2374C>G has been observed in individual(s) affected with Congenital Bilateral Absence Of The Vas Deferens, Cystic Fibrosis, or identified as having CFTR-related metabolic syndrome/CF screen positive, inconclusive diagnosis based on newborn screening programs (e.g. Vankeerberghen_1998, Dorfman_2010, Green_2010, Salinas_2023, Sadeghi_2025). However, these data do not allow any conclusion about variant significance. At least two publications report experimental evidence evaluating an impact on protein function (Vankeerberghen_1998, Bihler_2024). The most pronounced variant effect resulted in approximately 20% of normal chloride channel conductance relative to wild type (Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 38388235, 20059485, 20932301, 38695616, 25735457, 10878476, 12940920, 36409994, 9736778, 26277102, 29216686, 39532587). ClinVar contains an entry for this variant (Variation ID: 35840). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

CFTR-related disorder

Uncertain:1

May 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The CFTR c.2374C>G variant is predicted to result in the amino acid substitution p.Arg792Gly. This p.Arg792Gly change has been reported in a compound heterozygous individual with congenital bilateral absence of the vas deferens and functional studies suggest it may affect CFTR chloride channel function (Ravnik-Glavac et al. 2000. PubMed ID: 10878476; Vankeerberghen et al 1998. PubMed ID: 9736778). This variant is reported in 0.095% of alleles in individuals of Latino descent in gnomAD. This variant has an interpretation of uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/35840/). At this time, its clinical significance is uncertain due to the absence of conclusive functional and genetic evidence. -

Hereditary pancreatitis

Uncertain:1

May 04, 2021

Sema4, Sema4

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1

Uncertain:1

May 09, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.39

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.76

D;.;D;.

Eigen

Benign

-0.052

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.31

LIST_S2

Uncertain

0.91

D;D;D;D

M_CAP

Pathogenic

0.29

MetaRNN

Uncertain

0.43

T;T;T;T

MetaSVM

Pathogenic

0.90

MutationAssessor

Uncertain

2.3

M;.;.;.

PhyloP100

0.62

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.2

D;.;D;.

REVEL

Pathogenic

0.66

Sift

Benign

0.080

T;.;D;.

Sift4G

Pathogenic

0.0010

D;.;D;.

Polyphen

0.99

D;.;.;.

Vest4

0.92

MVP

0.99

MPC

0.0057

ClinPred

0.42

GERP RS

0.93

Varity_R

0.28

gMVP

0.64

Mutation Taster

=64/36

polymorphism

(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