rs145449046

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

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. R792Q) 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:10

Conservation

PhyloP100: 0.616

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2374C>G	p.Arg792Gly	missense_variant	14/27	ENST00000003084.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.2374C>G	p.Arg792Gly	missense_variant	14/27	1	NM_000492.4	P2	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

GnomAD3 exomes

AF:

0.000127

AC:

AN:

181308

Hom.:

AF XY:

0.000157

AC XY:

AN XY:

95510

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000944

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000281

Gnomad4 OTH exome

AF:

0.0000355

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152262

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000457

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 31, 2023	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 05, 2022	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. -

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 10, 2019	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 28, 2023	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. 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 0.00013 in 181538 control chromosomes, predominantly at a frequency of 0.00095 within the Latino subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Congenital Bilateral Absence Of The Vas Deferens or Cystic Fibrosis, allowing no conclusion about variant significance. c.2374C>G has been reported in the literature in individuals affected with Congenital Bilateral Absence Of The Vas Deferens and Cystic Fibrosis and has been subsequently cited by others (example, Vankeerberghen_1998, Ravnik-Glavac_2000, Dorfman_2010, Green_2010, Rowntree_2003, de Souza_2018, Yang_2015). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 30%-50% of normal activity for whole cell chloride currents measured in Xenopus laevis oocytes (Vakneerberghen_1998). The following publications have been ascertained in the context of this evaluation (PMID: 20059485, 20932301, 25735457, 10878476, 12940920, 9736778, 26277102, 29216686). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 12, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2019	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) -

Hereditary pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

Sema4, Sema4

May 04, 2021

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 09, 2022

- -

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

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;.;.;.

MutationTaster

Benign

1.0

N;N

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

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