rs397508395

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000492.4(CFTR):c.2552G>A(p.Arg851Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,612,712 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 Uncertain significance (★★).

Frequency

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

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:9

Conservation

PhyloP100: 9.06

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.30061668).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.2552G>A	p.Arg851Gln	missense_variant	15/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.2552G>A	p.Arg851Gln	missense_variant	15/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000461

AC:

AN:

151976

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000955

AC:

AN:

251312

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000924

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1460618

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

726716

show subpopulations

Gnomad4 AFR exome

AF:

0.0000897

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000354

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.0000332

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152094

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000329

Hom.:

Bravo

AF:

0.0000831

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3472

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	NxGen MDx	Jan 15, 2020	This variant (c.2552G>A) in exon 15 of CFTR results in p.Arg851Gln, transitioning from a polar side chain to a positively charged residue of similar size. This variant is present in gnomAD exomes and genomes at a very low allele frequency (PM2). Computational algorithms have generated pathogenic predictions for this variant (PP3). Additionally, this variant was reported in cis with c.2083dupG in 3 patients in 2 studies (Wu et al. PMID 10925568; Alper et al. PMID 12874665) and later observed by itself in a healthy adult (Guan et al. PMID 29997923). We interpret c.2552G>A to have uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jan 31, 2024	The p.R851Q variant (also known as c.2552G>A), located in coding exon 15 of the CFTR gene, results from a G to A substitution at nucleotide position 2552. The arginine at codon 851 is replaced by glutamine, an amino acid with highly similar properties. This variant was reported in one healthy control subject from a bronchiectasis cohort (Guan WJ et al. J Thorac Dis, 2018 May;10:2618-2630). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 10, 2022	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 851 of the CFTR protein (p.Arg851Gln). This variant is present in population databases (rs397508395, gnomAD 0.09%). This missense change has been observed in individual(s) with congenital absence of the vas deferens (PMID: 32777524). ClinVar contains an entry for this variant (Variation ID: 411119). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -

CFTR-related disorder

Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	May 07, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 26, 2023	The CFTR c.2552G>A variant is predicted to result in the amino acid substitution p.Arg851Gln. This variant was reported in an individual with congenital absence of vas deferens (Luo. 2021. PubMed ID: 32777524). This variant is reported in 0.095% of alleles in individuals of East Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-117235045-G-A). 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

Jul 01, 2024

Variant summary: CFTR c.2552G>A (p.Arg851Gln) results in a conservative amino acid change in 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 9.5e-05 in 251312 control chromosomes, predominantly at a frequency of 0.00092 within the East Asian subpopulation in the gnomAD database. This frequency is not higher than the estimated maximum expected for a pathogenic variant in CFTR causing Cystic Fibrosis (0.013), allowing no conclusion about variant significance. The variant, c.2552G>A, has been reported in the literature in heterozygous state in a Chinese patient affected with congenital absence of vas deferens (Luo_2021, Feng_2022), in addition, the variant was also published in heterozygous state in healthy subjects (Guan_2018, Cantu-Reyna_2021). These reports do not provide unequivocal conclusions about association of the variant with Cystic Fibrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Another missense affecting the same amino acid, p.Arg851Leu, is classified by our lab as likely pathogenic, which might indicate a functional importance for this residue. The following publications have been ascertained in the context of this evaluation (PMID: 29997923, 32777524, 34740355, 35913788). Seven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, partly without evidence for independent evaluation, and all classified the variant as uncertain significance. Additionally, a different missense variant affecting this variant has been classified as likely pathogenic by our lab, has been reported in CFTR patients, and was found to display <10% functional activity (PMID: 38388235). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 15, 2017

- -

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

Aug 06, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

T;.;T;.

Eigen

Pathogenic

0.81

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D;D

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.30

T;T;T;T

MetaSVM

Pathogenic

0.96

MutationAssessor

Uncertain

2.3

M;.;.;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.0

N;.;N;.

REVEL

Pathogenic

0.80

Sift

Benign

0.076

T;.;T;.

Sift4G

Pathogenic

0.0

D;.;D;.

Polyphen

1.0

D;.;.;.

Vest4

0.79

MVP

1.0

MPC

0.0043

ClinPred

0.14

GERP RS

5.3

Varity_R

0.30

gMVP

0.74

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