rs984281283

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000492.4(CFTR):​c.2395C>A​(p.Gln799Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000168 in 1,368,830 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

1
10
8

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.36
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CFTRNM_000492.4 linkc.2395C>A p.Gln799Lys missense_variant 14/27 ENST00000003084.11 NP_000483.3 P13569-1A0A024R730

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CFTRENST00000003084.11 linkc.2395C>A p.Gln799Lys missense_variant 14/271 NM_000492.4 ENSP00000003084.6 P13569-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000111
AC:
2
AN:
180086
Hom.:
0
AF XY:
0.0000105
AC XY:
1
AN XY:
94952
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:
0.0000227
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000168
AC:
23
AN:
1368830
Hom.:
0
Cov.:
32
AF XY:
0.0000179
AC XY:
12
AN XY:
671526
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:
0.0000215
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Cystic fibrosis Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 19, 2020The p.Q799K variant (also known as c.2395C>A), located in coding exon 14 of the CFTR gene, results from a C to A substitution at nucleotide position 2395. The glutamine at codon 799 is replaced by lysine, an amino acid with similar properties. This amino acid position is well 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.085
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
0.020
CADD
Benign
21
DANN
Benign
0.84
DEOGEN2
Uncertain
0.58
D;.;T;.
Eigen
Benign
-0.20
Eigen_PC
Benign
-0.18
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.84
T;T;T;T
M_CAP
Uncertain
0.19
D
MetaRNN
Uncertain
0.44
T;T;T;T
MetaSVM
Uncertain
0.48
D
MutationAssessor
Uncertain
2.3
M;.;.;.
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-0.86
N;.;N;.
REVEL
Uncertain
0.54
Sift
Uncertain
0.026
D;.;D;.
Sift4G
Uncertain
0.0020
D;.;D;.
Polyphen
0.053
B;.;.;.
Vest4
0.63
MutPred
0.41
Gain of ubiquitination at Q799 (P = 0.0066);.;.;.;
MVP
0.99
MPC
0.0039
ClinPred
0.27
T
GERP RS
4.4
Varity_R
0.17
gMVP
0.68

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.

Other links and lift over

dbSNP: rs984281283; hg19: chr7-117232616; COSMIC: COSV50134361; COSMIC: COSV50134361; API