NM_000492.4:c.2813T>G

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PP2PP3_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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V938L) has been classified as Uncertain significance.

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:5U:3

Conservation

PhyloP100: 6.09

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

cystic fibrosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Myriad Women’s Health, Orphanet
congenital bilateral absence of vas deferens
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hereditary chronic pancreatitis
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

CFTR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 22 uncertain in NM_000492.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 197 curated pathogenic missense variants (we use a threshold of 10). The gene has 46 curated benign missense variants. Gene score misZ: -3.1397 (below the threshold of 3.09). Trascript score misZ: -1.0868 (below the threshold of 3.09). GenCC associations: The gene is linked to hereditary chronic pancreatitis, cystic fibrosis, congenital bilateral absence of vas deferens.

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 VariationId is 35850.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFTR	NM_000492.4 link	c.2813T>G	p.Val938Gly	missense_variant	Exon 17 of 27	ENST00000003084.11	NP_000483.3	P13569-1A0A024R730

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CFTR	ENST00000003084.11 link	c.2813T>G	p.Val938Gly	missense_variant	Exon 17 of 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

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251412

AF XY:

0.0000221

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 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

African (AFR)

AF:

0.00

AC:

AN:

33468

American (AMR)

AF:

0.00

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000207

AC:

AN:

1111922

Other (OTH)

AF:

0.00

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000328

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41476

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000338

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:5Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cystic fibrosis

Pathogenic:2Uncertain:1

Jun 10, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jan 16, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Sep 29, 2021

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

CFTR-related disorder

Pathogenic:2

Aug 31, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

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. -

Jan 18, 2021

CFTR-France

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Congenital bilateral aplasia of vas deferens from CFTR mutation

Pathogenic:1

Dec 31, 2024

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Four of four 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, 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). 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, 38388235). ClinVar contains an entry for this variant (Variation ID: 35850). Based on the evidence outlined above, the variant was classified as pathogenic. -

not specified

Uncertain:1

Mar 16, 2017

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1

Oct 19, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

(source)

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;.;.;.;.

PhyloP100

6.1

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

Mutation Taster

=14/86

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over