chr7-117603686-G-C

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM5PP2PP3_Moderate

The NM_000492.4(CFTR):​c.2812G>C​(p.Val938Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,936 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 Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V938G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

7
8
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 4.96

Publications

3 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM1
In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000492.4
PM5
Other missense variant is known to change same aminoacid residue: 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 submission is: [Conflicting_classifications_of_pathogenicity].
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, 0.841

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CFTRNM_000492.4 linkc.2812G>C p.Val938Leu 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
CFTRENST00000003084.11 linkc.2812G>C p.Val938Leu missense_variant Exon 17 of 27 1 NM_000492.4 ENSP00000003084.6 P13569-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000796
AC:
2
AN:
251402
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461746
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727180
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33466
American (AMR)
AF:
0.0000447
AC:
2
AN:
44698
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26132
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53420
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1111914
Other (OTH)
AF:
0.0000331
AC:
2
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.455
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000197
AC:
3
AN:
152190
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74340
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41456
American (AMR)
AF:
0.000131
AC:
2
AN:
15272
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10616
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68032
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.492
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Cystic fibrosis Uncertain:4
Sep 05, 2021
Genome-Nilou Lab
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Jan 13, 2018
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces valine with leucine at codon 938 of the CFTR protein (p.Val938Leu). The valine residue is highly conserved and there is a small physicochemical difference between valine and leucine. This variant is present in population databases (rs749784731, ExAC 0.009%) but has not been reported in the literature in individuals with a CFTR-related disease. 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, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Sep 16, 2020
Natera, Inc.
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Aug 26, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.V938L variant (also known as c.2812G>C), located in coding exon 17 of the CFTR gene, results from a G to C substitution at nucleotide position 2812. The valine at codon 938 is replaced by leucine, an amino acid with highly similar properties. 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 alteration remains unclear. -

not provided Uncertain:1
Jul 23, 2024
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The CFTR c.2812G>C (p.Val938Leu) variant, to the best of our knowledge, has not been reported in the published literature. A different variant causing the same amino acid substitution, c.2812G>T (p.Val938Leu), has been reported in individuals with CBAVD (congenital absence of the vas deferens) (PMID: 32777524 (2021)), and in an infant with cystic fibrosis (CF) who carried a CF-causing variant on the opposite chromosome (PMIDs: 37477516 (2023), 35858753 (2022)). The frequency of the c.2812G>C (p.Val938Leu) variant in the general population, 0.000008 (2/251402 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 damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Cystic fibrosis;C0238339:Hereditary pancreatitis;C0403814:Congenital bilateral aplasia of vas deferens from CFTR mutation;C2749757:Bronchiectasis with or without elevated sweat chloride 1 Uncertain:1
Jul 23, 2021
Fulgent Genetics, Fulgent Genetics
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
Uncertain
0.50
BayesDel_addAF
Uncertain
0.11
D
BayesDel_noAF
Uncertain
0.10
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.57
D;.;.;T;.
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;D;D;D
M_CAP
Pathogenic
0.54
D
MetaRNN
Pathogenic
0.84
D;D;D;D;D
MetaSVM
Uncertain
0.62
D
MutationAssessor
Benign
1.9
L;.;.;.;.
PhyloP100
5.0
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-1.2
N;.;.;N;.
REVEL
Uncertain
0.64
Sift
Benign
0.062
T;.;.;T;.
Sift4G
Pathogenic
0.0
D;.;.;D;.
Polyphen
0.98
D;.;.;.;.
Vest4
0.69
MutPred
0.77
Gain of methylation at R933 (P = 0.143);.;.;.;.;
MVP
1.0
MPC
0.0054
ClinPred
0.65
D
GERP RS
5.8
Varity_R
0.70
gMVP
0.92
Mutation Taster
=24/76
disease causing

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

Other links and lift over

dbSNP: rs749784731; hg19: chr7-117243740; API