chr7-117603730-G-C

Position:

chr7-117603730-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3_ModeratePP5

The NM_000492.4(CFTR):c.2856G>C(p.Met952Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000052 in 1,614,016 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:18U:3O:1

Conservation

PhyloP100: 9.76

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 Likely_pathogenic. Variant got 7 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 50) in uniprot entity CFTR_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.865

PP5

Variant 7-117603730-G-C is Pathogenic according to our data. Variant chr7-117603730-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 53580.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, not_provided=1, Pathogenic=7, Likely_pathogenic=10}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2856G>C	p.Met952Ile	missense_variant	17/27	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.2856G>C	p.Met952Ile	missense_variant	17/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000796

AC:

AN:

251352

Hom.:

AF XY:

0.000125

AC XY:

AN XY:

135830

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000869

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.0000980

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000114

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000499

AC:

AN:

1461728

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727160

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000450

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152288

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000836

Hom.:

Bravo

AF:

0.0000718

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:18Uncertain:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:6Uncertain:3Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jun 19, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 08, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 23, 2024	The p.M952I variant (also known as c.2856G>C), located in coding exon 17 of the CFTR gene, results from a G to C substitution at nucleotide position 2856. The methionine at codon 952 is replaced by isoleucine, an amino acid with highly similar properties. CFTR p.M952I (c.2586G>A or c.2586G>C) was originally identified in an individual with severe pulmonary disease, pancreatic insufficiency, and an elevated sweat chloride level; a second CFTR alteration was not identified (Desgeorges M et al. Hum. Genet., 1997 Aug;100:279-83). This variant was also detected in conjunction with pathogenic CFTR mutations in individuals with idiopathic chronic pancreatitis and congenital bilateral absence of the vas deferens (CBAVD) (Uzun S et al. Tohoku J. Exp. Med., 2005 Dec;207:279-85; Ratbi I et al. Hum. Reprod. 2007;22(5):1285-91; Steiner B et al. Hum. Mutat. 2011 Aug;32(8):912-20; Akinsal EC et al. Andrologia, 2018 Feb; Rudnik-Schöneborn S et al. Hum Reprod, 2021 02;36:551-559). 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 available evidence to date, this variant is unlikely to be causative of classic cystic fibrosis; however, it likely contributes to the development of a CFTR-related disorder. This alteration is thus classified as likely pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	The CFTR c.2856G>C (p.Met952Ile) missense variant has been reported in at least six studies and is found in a total of ten individuals with CFTR-related disorders. The p.Met952Ile variant was identified in a compound heterozygous state in five individuals with congenital bilateral absence of the vas deferens (CBAVD), four of whom were identified with the p.Phe508del variant in trans (Uzun et al. 2005; Steiner et al. 2011). The p.Met952Ile was also identified in a heterozygous state in three individuals with cystic fibrosis, one individual with oligospermia, and one individual with CBAVD (Desgeorges et al. 1997; Onay et al. 1998; Gallati et al. 2009; Steiner et al. 2011; KÅ™enkovÃ¡ et al. 2013). The p.Met952Ile variant was absent from 415 controls but is reported at a frequency of 0.00012 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence, the p.Met952Ile variant is classified as likely pathogenic for CFTR-related disorders, and has most commonly been reported in patients with CBAVD. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 18, 2024	This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 952 of the CFTR protein (p.Met952Ile). This variant is present in population databases (rs151048781, gnomAD 0.01%). This missense change has been observed in individual(s) with congenital bilateral absence of the vas deferens or cystic fibrosis (PMID: 10200050, 15070876, 15287992, 16272798, 16980811, 21520337, 23276700). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 53580). 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 expected to disrupt CFTR protein function with a positive predictive value of 80%. This variant disrupts the p.Met952 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 10875853), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Oct 21, 2024	Criteria applied: PM3_STR,PP3_MOD -
Uncertain significance, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 02, 2020	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 29, 2024	- -

not provided

Pathogenic:5

Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 17, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 30, 2024	The CFTR c.2856G>C (p.Met952Ile) variant has been reported in multiple individuals with congenital bilateral absence of the vas deferens (CBAVD) who were also positive for a pathogenic variant in the CFTR gene known to be associated with cystic fibrosis (CF) (PMID: 15070876 (2004), 16272798 (2005), 17329263 (2007), 21520337 (2011), 29484681 (2018)). This variant has been reported in individuals with a diagnosis of CF, but a second CFTR variant was either not identified or the genotype of the affected individual was not reported (PMID: 9254864 (1997), 11446424 (2001), 15948195 (2005), 16617247 (2006), 28544683 (2017)). It has also been reported in individuals with classic CF who were positive for two other variants that prevent the synthesis of CFTR protein (PMID: 16980811 (2006), 23276700 (2013)). The frequency of this variant in the general population (0.00011, 13/113696 chromosomes (Genome Aggregation Database (http://gnomad.broadinstitute.org))) is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is deleterious. Based on the available information, this variant is classified as a likely pathogenic variant that is associated with CFTR-related disorders (CFTR-RD). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	CFTR: PM3:Very Strong, PS1, PM2, PM5 -
Likely pathogenic, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 23, 2020	- -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Dec 09, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 11, 2023	Variant summary: CFTR c.2856G>C (p.Met952Ile) results in a conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) 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 8e-05 in 251352 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in CFTR causing Congenital Bilateral Absence Of The Vas Deferens (8e-05 vs 0.013), allowing no conclusion about variant significance. c.2856G>C has been reported in the literature in compound heterozygosity with another pathogenic variant in multiple individuals affected with Congenital Bilateral Absence Of The Vas Deferens (CBAVD; e.g. de Meeus_1997, Claustres_2004, Dayangac_2004, Uzun_2005, Ratbi_2007, Steiner_2011, Akinsal_2018). These data indicate that the variant is very likely to be associated with CBAVD disease. The variant has also been reported in multiple individuals affected with cystic fibrosis, however in at least one case, two additional pathogenic mutations in CFTR were found (phase not specified; e.g. Kammesheidt_2006), and in others, a second pathogenic mutation was not reported, and therefore evidence for causality in these cases could not be established (e.g. Desgeorges_1997, Onay_1998, Quint_2005, Soltysova_2017). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A different variant that creates the same amino acid change has been reported as pathogenic for CBAVD by our lab (c.2856G>A). The following publications have been ascertained in the context of this evaluation (PMID: 29484681, 17975025, 15287992, 15070876, 9254864, 20797923, 20021716, 20100616, 16980811, 25033378, 9521595, 10601093, 15948195, 17329263, 33374015, 26437683, 28544683, 21520337, 16272798, 16617247, 10200050). 15 clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments: 12 submitters classified the variant as likely pathogenic/pathogenic while 3 classified as VUS. Based on the evidence outlined above, the variant was classified as pathogenic in association with CBAVD. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -

not specified

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 08, 2018

The CFTR c.2856G>C; p.Met952Ile variant (rs151048781) is reported in the literature in multiple individuals with congenital absence of the vas deferens (CBAVD), including in individuals with a second pathogenic CFTR variant (Dayangac 2004, Ratbi 2007, Steiner 2011, Uzun 2007). While this variant has also been reported in several individuals with cystic fibrosis (CF), one individual already carried two other pathogenic variants (Desgeorges 2004, Krenkova 2013). The p.Met952Ile variant is reported in ClinVar (Variation ID: 53580) and is found in the general population with an overall allele frequency of 0.008% (20/251352 alleles) in the Genome Aggregation Database. The methionine at codon 952 is highly conserved, but computational analyses (SIFT: tolerated, PolyPhen-2: damaging) predict conflicting effects of this variant on protein structure/function. However, another variant at this codon (p.Met952Thr) has been reported in individuals with CBAVD and is considered pathogenic (Casals 2000, Gilljam 1997, Wilschanski 2006). Though it is unclear if the p.Met952Ile variant causes classic CF, due to its strong association with CBAVD, this variant is considered to be likely pathogenic. References: Casals T et al. Heterogeneity for mutations in the CFTR gene and clinical correlations in patients with congenital absence of the vas deferens. Hum Reprod. 2000; 15(7):1476-83. Dayangac D et al. Mutations of the CFTR gene in Turkish patients with congenital bilateral absence of the vas deferens. Hum Reprod. 2004 May;19(5):1094-100. Desgeorges M et al. Cystic fibrosis in Lebanon: distribution of CFTR mutations among Arab communities. Hum Genet. 1997 Aug;100(2):279-83. Gilljam M et al. Airway inflammation and infection in congenital bilateral absence of the vas deferens. Am J Respir Crit Care Med. 2004; 169(2):174-9. Krenkova P et al. Distribution of CFTR mutations in the Czech population: positive impact of integrated clinical and laboratory expertise, detection of novel/de novo alleles and relevance for related/derived populations. J Cyst Fibros. 2013 Sep;12(5):532-7. Ratbi I et al. Detection of cystic fibrosis transmembrane conductance regulator (CFTR) gene rearrangements enriches the mutation spectrum in congenital bilateral absence of the vas deferens and impacts on genetic counselling. Hum Reprod. 2007 May;22(5):1285-91. Steiner B et al. Common CFTR haplotypes and susceptibility to chronic pancreatitis and congenital bilateral absence of the vas deferens. Hum Mutat. 2011 Aug;32(8):912-20. Uzun S et al. Cystic fibrosis transmembrane conductance regulator gene mutations in infertile males with congenital bilateral absence of the vas deferens. Tohoku J Exp Med. 2005 Dec;207(4):279-85 Wilschanski M et al. Mutations in the cystic fibrosis transmembrane regulator gene and in vivo transepithelial potentials. Am J Respir Crit Care Med. 2006; 174(7):787-94. -

CFTR-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

curation

CFTR-France

Jan 29, 2018

- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jan 29, 2024

- -

Bronchiectasis with or without elevated sweat chloride 1

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

D;.;.;D;.

Eigen

Pathogenic

0.88

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D;D

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.87

D;D;D;D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Pathogenic

3.0

M;.;.;.;.

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-2.0

N;.;.;N;.

REVEL

Pathogenic

0.82

Sift

Benign

0.14

T;.;.;T;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

0.99

D;.;.;.;.

Vest4

0.95

MutPred

0.88

Gain of catalytic residue at L957 (P = 0.0495);.;.;.;.;

MVP

1.0

MPC

0.0079

ClinPred

0.86

GERP RS

5.0

Varity_R

0.81

gMVP

0.96

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