rs193922511

Positions:

chr7-117603687-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5

The NM_000492.4(CFTR):c.2813T>G(p.Val938Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000173 in 1,613,998 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 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:3

Conservation

PhyloP100: 6.09

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 9 ACMG points.

PM1

In a domain ABC transmembrane type-1 2 (size 296) in uniprot entity CFTR_HUMAN there are 53 pathogenic changes around while only 8 benign (87%) in NM_000492.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.971

PP5

Variant 7-117603687-T-G is Pathogenic according to our data. Variant chr7-117603687-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35850.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CFTR	NM_000492.4 linkuse as main transcript	c.2813T>G	p.Val938Gly	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.2813T>G	p.Val938Gly	missense_variant	17/27	1	NM_000492.4	ENSP00000003084.6		P13569-1

Frequencies

GnomAD3 genomes

AF:

0.0000328

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251412

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461758

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727178

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:

0.0000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000557

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

CFTR-related disorder

Pathogenic:2

Pathogenic, criteria provided, single submitter	curation	CFTR-France	Jan 18, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Aug 31, 2024	The CFTR c.2813T>G variant is predicted to result in the amino acid substitution p.Val938Gly. This variant was reported in multiple individuals with congenital absence of vas deferens (CAVD) (Doerk et al 1997. PubMed ID: 9272157; Ratbi et al. 2007. PubMed ID: 17329263). It has also been reported along with a second pathogenic CFTR variant in a study of male patients with fertility problems (Rudnik-Schöneborn et al. 2021. PubMed ID: 33374015), an individual with idiopathic chronic pancreatitis (Sofia et al. 2016. PubMed ID: 27264265), an individual with abnormal newborn screening results for cystic fibrosis (Bozdogan et al. 2021. PubMed ID: 33572515), and along with the p.Phe508del variant in an individual with pancreatic sufficient cystic fibrosis (De Wachter et al 2017. PubMed ID: 28830496). Alternate substitutions of the same amino acid (p.Val938Leu) have been reported in individuals with CAVD (Luo et al. 2020. PubMed ID: 32777524; Table S1, Fang et al. 2022. PubMed ID: 36437957). An experimental study suggests the p.Vla938Gly substitution impacts protein function (Table S1, Bihler et al. 2024. PubMed ID: 38388235). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. Taken together, this variant is interpreted as pathogenic. -

Cystic fibrosis

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 10, 2024	The p.V938G variant (also known as c.2813T>G), located in coding exon 17 of the CFTR gene, results from a T to G substitution at nucleotide position 2813. The valine at codon 938 is replaced by glycine, an amino acid with dissimilar properties. This variant was identified in two individuals; one individual was homozygous and presented with congenital unilateral absence of the vas deferens (CUAVD) and asthma bronchiale. The other individual was heterozygous for this variant as well as a frameshift alteration and presented with congenital bilateral absence of the vas deferens (CBAVD) and a borderline sweat chloride level; the phase of these alterations was not provided (Dörk T et al. Hum. Genet. 1997 Sep; 100(3-4):365-77). In another study, this variant was observed in one individual with CBAVD and a gross deletion (Ratbi I et al. Hum. Reprod. 2007 May;22(5):1285-91). 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 variant remains unclear. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 938 of the CFTR protein (p.Val938Gly). This variant is present in population databases (rs193922511, gnomAD 0.003%). This missense change has been observed in individuals with cystic fibrosis, unilateral congenital absence of the vas deferens, or bilateral absence of the vas deferens (PMID: 9272157, 17329263, 28603918). ClinVar contains an entry for this variant (Variation ID: 35850). 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 with a negative predictive value of 80%. This variant disrupts the p.Val938 amino acid residue in CFTR. Other variant(s) that disrupt this residue have been observed in individuals with CFTR-related conditions (PMID: 9272157, 17329263, 28603918, 32777524, 36437957), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Oct 06, 2023

Variant summary: CFTR c.2813T>G (p.Val938Gly) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 251512 control chromosomes (gnomAD), which does not exceed the estimated maximal expected allele frequency for a pathogenic CFTR variant causing CF/CFTR-RD/CBAVD. c.2813T>G has been reported in the literature in multiple individuals affected with Congenital Absence of the Vas Deferens (CBAVD and CUAVD)/infertility, once in a homozygous state, and others in a compound heterozygous state with other pathogenic CFTR variants (e.g., Dork_1997, Marcelli_2006, Robin_2007, Ratbi_2007, Rudnik-Schoneborn_2021). Because CBAVD/CUAVD is often found in patients with either one severe and one mildly pathogenic variant or two mildly pathogenic variants, the presence of this variant in CBAVD/CUAVD patients in trans with severe variants suggests that the variant may be a "mild" variant that contributes to CFTR-related disease. This variant has also been reported in patients screened for cystic fibrosis, idiopathic pancreatitis and other CFTR-related diseases, however not in well phenotyped cases of classic cystic fibrosis associated with pancreatic/pulmonary insufficiency (e.g., Sands_2015, Sofia_2016, De Wachter_2017, Bozdogan_2021, Nykamp_2021). At least one publication reports experimental evidence evaluating an impact on protein function, finding that the variant results in approximately 35% of normal chloride channel conductance relative to wild type (e.g., Bihler_2023 (bioRxiv, no PMID)). The following publications have been ascertained in the context of this evaluation (PMID: 33572515, 28830496, 18685558, 20059485, 9272157, 17175965, 34196078, 17329263, 17507277, 33374015, 26003066, 31674704, 27264265, 10755189, 26277102). Five submitters have reported clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments (VUS, n = 3; likely pathogenic, n = 1; pathogenic, n = 1). Based on the evidence outlined above, the variant was classified as pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Quest Diagnostics Nichols Institute San Juan Capistrano

Mar 16, 2017

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 19, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.34

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.;.;D;.

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D;D;D;D

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Uncertain

0.78

MutationAssessor

Uncertain

2.5

M;.;.;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.7

D;.;.;D;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.;.;D;.

Sift4G

Pathogenic

0.0

D;.;.;D;.

Polyphen

1.0

D;.;.;.;.

Vest4

0.65

MutPred

0.88

Loss of stability (P = 2e-04);.;.;.;.;

MVP

1.0

MPC

0.0074

ClinPred

0.98

GERP RS

4.6

Varity_R

0.96

gMVP

0.94

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