rs138069616

Positions:

chr7-117592559-C-T

Variant summary

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

The NM_000492.4(CFTR):c.2392C>T(p.Pro798Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000441 in 1,520,656 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 4.37

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	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2392C>T	p.Pro798Ser	missense_variant	14/27	ENST00000003084.11	NP_000483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.2392C>T	p.Pro798Ser	missense_variant	14/27	1	NM_000492.4	ENSP00000003084	P2	P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000111

AC:

AN:

180160

Hom.:

AF XY:

0.0000105

AC XY:

AN XY:

94956

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000481

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:

0.0000113

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000468

AC:

AN:

1368460

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

671326

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.0000552

Gnomad4 OTH exome

AF:

0.0000888

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

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	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 07, 2022	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 798 of the CFTR protein (p.Pro798Ser). This variant is present in population databases (rs138069616, gnomAD 0.005%). This missense change has been observed in individual(s) with CFTR-related conditions (PMID: 25735457). ClinVar contains an entry for this variant (Variation ID: 35841). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 23, 2023	The p.P798S variant (also known as c.2392C>T), located in coding exon 14 of the CFTR gene, results from a C to T substitution at nucleotide position 2392. The proline at codon 798 is replaced by serine, an amino acid with similar properties. An individual diagnosed with cystic fibrosis was reported to be heterozygous for this variant, in addition to the p.F508del pathogenic mutation and three other variants of unknown significance (p.R74W, p.D1270N, p.G921E). The phase (cis vs trans) of these alterations was not determined (Sharma G, Pediatr. Pulmonol. 2013 Mar; 48(3):236-44). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jun 15, 2022	CFTR c.2392C>T has been identified in multiple individuals with features of cystic fibrosis; however, each individual carries multiple CFTR variants and the contribution of this variant to their phenotype is uncertain. This CFTR variant (rs138069616) is rare (<0.1%) in a large population dataset (gnomAD: 2/180160 total alleles; 0.001%; no homozygotes) and it has been reported in ClinVar (Variation ID: 35841). Of three bioinformatics tools queried, two predict that this substitution would be tolerated, while one predicts that it would be damaging. The proline residue at this position is conserved in most species assessed, although a serine is present at this position in Xenopus tropicalis. We consider the clinical significance of CFTR c.2392C>T to be uncertain at this time. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 29, 2020	The CFTR c.2392C>T; p.Pro798Ser variant (rs138069616) is reported in the literature in one individual with cystic fibrosis who also carried additional pathogenic variants (Sharma 2013), but the phase and significance of the variants were not determined. The variant is reported in the ClinVar database (Variation ID: 35841) and is listed in the general population with an overall allele frequency of 0.001% (2/180,160 alleles) in the Genome Aggregation Database. The proline at codon 798 is moderately conserved and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Pro798Ser variant is uncertain at this time. References: Sharma G et al. Reduced Arylsulfatase B Activity in Leukocytes From Cystic Fibrosis Patients. Pediatr Pulmonol. 2013 Mar;48(3):236-44. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 27, 2017	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2023	Identified in a patient with cystic fibrosis in published literature; however, this individual also harbored several other CFTR variants of unknown phase (Sharma et al., 2013); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25735457, 22550062) -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 23, 2022

Variant summary: CFTR c.2392C>T (p.Pro798Ser) 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 1.1e-05 in 180160 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2392C>T has been observed in an internal specimen in cis with R74W, D1270N, and G921E (all paternally inherited) in a child diagnosed with Cystic Fibrosis (CF), who carried the common disease variant, F508del, in trans. This complex genotype (phase not specified) has also been reported in the literature in an individual affected with CF (Sharma_2013). The co-occurring complex allele, c.[220C>T;3808G>A] (p.[Arg74Trp;Asp1270Asn]), has been classified as a VUS-possibly pathogenic variant by our laboratory (Variation ID: 977735). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

CFTR-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 14, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.098

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.76

D;.;D;.

Eigen

Benign

0.061

Eigen_PC

Benign

0.13

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Pathogenic

0.34

MetaRNN

Uncertain

0.55

D;D;D;D

MetaSVM

Uncertain

0.59

MutationAssessor

Benign

1.8

L;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.43

PROVEAN

Uncertain

-3.0

D;.;D;.

REVEL

Uncertain

0.48

Sift

Benign

0.076

T;.;T;.

Sift4G

Benign

0.14

T;.;T;.

Polyphen

0.15

B;.;.;.

Vest4

0.38

MVP

0.98

MPC

0.0058

ClinPred

0.40

GERP RS

5.3

Varity_R

0.21

gMVP

0.58

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