rs1800086

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP6BS2_Supporting

The NM_000492.4(CFTR):c.1052C>G(p.Thr351Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00018 in 1,614,014 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00018 ( 2 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:12B:2

Conservation

PhyloP100: 7.43

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 0 ACMG points.

PM1

In a transmembrane_region Helical; Name=6 (size 18) in uniprot entity CFTR_HUMAN there are 9 pathogenic changes around while only 1 benign (90%) in NM_000492.4

BP6

Variant 7-117540282-C-G is Benign according to our data. Variant chr7-117540282-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53174.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=11, Benign=1}. Variant chr7-117540282-C-G is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.1052C>G	p.Thr351Ser	missense_variant	8/27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 linkuse as main transcript	c.1052C>G	p.Thr351Ser	missense_variant	8/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.000223

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000183

AC:

AN:

251162

Hom.:

AF XY:

0.000169

AC XY:

AN XY:

135728

show subpopulations

Gnomad AFR exome

AF:

0.000308

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.000695

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000194

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000176

AC:

257

AN:

1461732

Hom.:

Cov.:

AF XY:

0.000171

AC XY:

124

AN XY:

727178

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.000536

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000150

Gnomad4 OTH exome

AF:

0.000613

GnomAD4 genome

AF:

0.000223

AC:

AN:

152282

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000223

Hom.:

Bravo

AF:

0.000280

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000173

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:12Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Uncertain:5Benign:1

Uncertain significance, criteria provided, single submitter	research	Programa de Pós-Graduação em Genética e Biologia Molecular, Universidade Federal do Rio Grande do Sul	Oct 11, 2021	This imprecision led to the belief that this variant is pathogenic. Despite this variant has been classified and reclassified over the course of time as pathogenic and lately as likely pathogenic (by Mendelics and Invitae), new functional evidence has shown that this variant does not alter CFTR function even when located in the same allele (in cis) as NM_000492.4(CFTR):2552G>T; p.Arg851Leu) and in trans with the most common pathogenic variant p.Phe508del (NM_000492.4(CFTR):1521_1523delCTT). Although in a pathogenic range due to its very low frequency in public databases (1000 Genomes, GnomAd Exons, GnomAd Genomes, etc., in people from different ethnicities), the aminoacid change promoted by this missense variant is practically synonymous for both amino acids residues are polar uncharged (at physiological pH), conserving the hydroxyl group in the side chain of this amino acid, basically having absent to little impact in the CFTR protein. Also, there is another missense variant in the same nucleotide position which has been classified as having uncertain significance (NM_000492.4(CFTR):c.1052C>T; p.Thr351Ile). Besides, prediction tools do not fully agree when predicting the deleteriousness of this variant. Therefore, the controversial data existing to date regarding this variant leads to the classification of uncertain significance. Brief Medical History: the patient was diagnosed with NBS and treated with pancreatic enzymes until the age of 2-3 y.o. The mother decided to stop giving any medication. Since then, the patient presented normal thrive and growth, normal stature, and was eutrophic throughout her life, which would not be expected given the patient's genotype. The patient is now 22 y.o. and has no history of chronic lung infections nor exacerbations or any other features compatible with Cystic Fibrosis. Sweat chloride tests have always been within borderline range (30-59 mM). Also, the patient is pancreatic-sufficient. In January 2020, the patient provided stool samples. Fecal elastase-1 levels in feces samples are within the normal range of the assay, which is a biomarker of pancreatic exocrine sufficiency. Other biochemical and hematological measurements to verify liver function were also normal throughout the patient's life. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 06, 2022	This sequence change replaces threonine, which is neutral and polar, with serine, which is neutral and polar, at codon 351 of the CFTR protein (p.Thr351Ser). This variant is present in population databases (rs1800086, gnomAD 0.07%). This missense change has been observed in individual(s) with pancreatitis, congenital absence of the vas deferens (CAVD), and mild or atypical cysitic fibrosis (PMID: 2395135, 9272157, 15858154, 16128988, 23670503). ClinVar contains an entry for this variant (Variation ID: 53174). 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. 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. -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Dec 07, 2022	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Nov 05, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	May 28, 2020	- -

not provided

Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 18, 2023	PP3, PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Feb 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 22, 2018	- -

CFTR-related disorder

Pathogenic:1Uncertain:1Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 19, 2024	The CFTR c.1052C>G variant is predicted to result in the amino acid substitution p.Thr351Ser. This variant has been reported in the heterozygous state in an individual with idiopathic chronic pancreatitis, an individual with CBAVD, and in an individual with clinical manifestations consistent with the spectrum of CF (Table S1, Masson. 2013. PubMed ID: 23951356; Larriba et al. 2005 PubMed ID: 16128988; Schrijver et al. 2005. PubMed ID: 15858154). This variant has also been reported in the compound heterozygous state with a p.Phe508del variant in an individual with CBAVD (Doerk et al. 1997. Table 3 PubMed ID: 9272157) and in the homozygous state (and in cis with another CFTR variant) in an individual with a CFTR-related disorder ( Table S3, Trujillano. 2013. PubMed ID: 23687349). In one individual with CF, this variant was one of three identified, and was in cis with a p.Phe508del variant (Dal'Maso et al. 2013 Table 3 PubMed ID: 23670503). To our knowledge, no functional or family studies are available to confirm the pathogenicity of the c.1052C>G change. This variant is reported in 0.068% of alleles in individuals of Ashkenazi Jewish descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 rule this variant out of causing disease. Therefore, this variant is classified as benign. -
Likely pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	May 28, 2020	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 20, 2024

Variant summary: CFTR c.1052C>G (p.Thr351Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00019 in 251742 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in CFTR causing Cystic Fibrosis (0.00019 vs 0.013), allowing no conclusion about variant significance. c.1052C>G has been reported in the literature in individuals affected with Cystic Fibrosis, CBAVD, chronic pancreatitis and diffuse bronchiectasis, without strong evidence of causality (Mercier_1993, Dork_1997, Schrijver_2005, Bienvenu_2010, de Cid_2010, Dal Maso_2013, Masson_2013, Trujillano_2013, Grangeia_2018, Rispoli_2020, da Silva Filho_2021). These reports do not provide unequivocal conclusions about association of the variant with disease. At-least two co-occurrences in cis with other pathogenic variants have been reported (e.g. CFTR c.3484C>T, p.Arg1162X; CFTR c.1521_1523del, p.Phe508del) (Mercier_1993, Dal Maso_2013), providing supporting evidence for a benign role. One of these reports was in an obligate carrier father of an individual with CF (in cis with p.Arg1162X, Mercier_1993) while the other was in an individual reportedly affected with CF who harbored a non-informative genotype attributed to a synonymous variant (p.Pro1290=) in trans (in cis with p.Phe508del, Del Maso_2013). At least two publications report experimental evidence evaluating an impact on protein function (Bergougnoux_2023, Bihler_2024). The variant did not show any deleterious impact on mRNA or protein expression and Western blot results were not suggestive of a folding defect. However, the most pronounced variant effect resulted in approximately 46% of normal chloride channel conductance relative to wild type (e.g. Bihler_2024). The following publications have been ascertained in the context of this evaluation (PMID: 20167849, 33572515, 23670503, 20059485, 9272157, 18716917, 29589582, 16128988, 23951356, 8477260, 25735457, 32185651, 15858154, 23687349, 32819855, 19812525, 36567205, 38388235). ClinVar contains an entry for this variant (Variation ID: 53174). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Hereditary pancreatitis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Aug 31, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Uncertain

0.092

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.68

D;.;.;T;.

Eigen

Pathogenic

0.69

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;D;D;D

M_CAP

Pathogenic

0.69

MetaRNN

Uncertain

0.54

D;D;D;D;D

MetaSVM

Uncertain

0.65

MutationAssessor

Uncertain

2.3

M;.;.;.;M

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.1

N;.;.;N;.

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0070

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

0.95

P;.;.;.;.

Vest4

0.85

MutPred

0.82

Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);.;Gain of helix (P = 0.132);

MVP

0.99

MPC

0.0052

ClinPred

0.21

GERP RS

5.3

Varity_R

0.80

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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