Menu
GeneBe

rs397508753

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePM1PM2PP3_Strong

The NM_000492.4(CFTR):c.558C>A(p.Asn186Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000035 in 1,430,278 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000035 ( 0 hom. )

Consequence

CFTR
NM_000492.4 missense

Scores

4
12
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.880
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 Pathogenic. Variant got 10 ACMG points.

PS1
Transcript NM_000492.4 (CFTR) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 558712
PM1
In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000492.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.942

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CFTRNM_000492.4 linkuse as main transcriptc.558C>A p.Asn186Lys missense_variant 5/27 ENST00000003084.11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CFTRENST00000003084.11 linkuse as main transcriptc.558C>A p.Asn186Lys missense_variant 5/271 NM_000492.4 P2P13569-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000350
AC:
5
AN:
1430278
Hom.:
0
Cov.:
25
AF XY:
0.00000420
AC XY:
3
AN XY:
713662
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000253
Gnomad4 SAS exome
AF:
0.0000467
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.80
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.060
Cadd
Benign
23
Dann
Uncertain
1.0
DEOGEN2
Uncertain
0.69
D;.;.;.
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.96
D;D;D;D
M_CAP
Pathogenic
0.73
D
MetaRNN
Pathogenic
0.94
D;D;D;D
MetaSVM
Pathogenic
0.82
D
MutationAssessor
Uncertain
2.7
M;.;.;M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.79
T
PROVEAN
Benign
-0.51
N;.;.;.
REVEL
Uncertain
0.63
Sift
Benign
0.095
T;.;.;.
Sift4G
Uncertain
0.046
D;.;.;.
Polyphen
0.95
P;.;.;.
Vest4
0.88
MutPred
0.86
Gain of ubiquitination at N186 (P = 0.0185);Gain of ubiquitination at N186 (P = 0.0185);Gain of ubiquitination at N186 (P = 0.0185);Gain of ubiquitination at N186 (P = 0.0185);
MVP
0.97
MPC
0.015
ClinPred
0.94
D
GERP RS
4.6
Varity_R
0.69
gMVP
0.90

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs397508753; hg19: chr7-117174398; API