chr7-117534344-C-A
Variant summary
Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PS1_ModeratePM1PM2PP2PP3_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. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.
Frequency
Consequence
NM_000492.4 missense
Scores
Clinical Significance
Conservation
Publications
- cystic fibrosisInheritance: 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 deferensInheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
- hereditary chronic pancreatitisInheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
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ACMG classification
Our verdict: Pathogenic. The variant received 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CFTR | NM_000492.4 | c.558C>A | p.Asn186Lys | missense_variant | Exon 5 of 27 | ENST00000003084.11 | NP_000483.3 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome AF: 0.00000350 AC: 5AN: 1430278Hom.: 0 Cov.: 25 AF XY: 0.00000420 AC XY: 3AN XY: 713662 show subpopulations
Age Distribution
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: CFTR c.558C>A (p.Asn186Lys) results in a non-conservative amino acid change located in the first transmembrane domain (IPR011527) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 31400 control chromosomes. c.558C>A has been reported in the literature in two individuals affected with Cystic Fibrosis or Cystic Fibrosis related Bronchiectasis (Claustres_2017, Sickkids database). A third case carring the current variant at a heterozygous state was also mentioned, but not enough clinical info or second variant were provided (Claustres_2017). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. ClinVar contains an entry for this variant (Variation ID: 3391202). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Cystic fibrosis Uncertain:1
The observed missense c.558C>Ap.Asn186Lys variant in CFTR gene has not been reported previously as a pathogenic variant nor a benign variant, to our knowledge. The p.Asn186Lys variant is absent in gnomAD Exomes. This variant has not been submitted to the ClinVar database. Multiple lines of computational evidences Polyphen - Probably damaging, SIFT - Tolerated and MutationTaster - Disease causing predict conflicting evidence on protein structure and function for this variant. The reference amino acid change at this position on CFTR gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Asn at position 186 is changed to a Lys changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as a Variant of Uncertain Significance VUS. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at