chr12-52897488-C-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_002273.4(KRT8):c.1392G>T(p.Lys464Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,599,194 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 (★★).
Frequency
Consequence
NM_002273.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KRT8 | NM_002273.4 | c.1392G>T | p.Lys464Asn | missense_variant | Exon 8 of 8 | ENST00000692008.1 | NP_002264.1 | |
KRT8 | NM_001256282.2 | c.1476G>T | p.Lys492Asn | missense_variant | Exon 9 of 9 | NP_001243211.1 | ||
KRT8 | NM_001256293.2 | c.1392G>T | p.Lys464Asn | missense_variant | Exon 9 of 9 | NP_001243222.1 | ||
KRT8 | NR_045962.2 | n.1843G>T | non_coding_transcript_exon_variant | Exon 9 of 9 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000164 AC: 25AN: 152240Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000114 AC: 27AN: 237292Hom.: 0 AF XY: 0.000139 AC XY: 18AN XY: 129392
GnomAD4 exome AF: 0.000286 AC: 414AN: 1446954Hom.: 0 Cov.: 34 AF XY: 0.000264 AC XY: 190AN XY: 720252
GnomAD4 genome AF: 0.000164 AC: 25AN: 152240Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74384
ClinVar
Submissions by phenotype
not provided Uncertain:1Other:1
The K464N variant in the KRT8 gene has been reported previously in an individual with ulcerative colitis who also had a family history of irritable bowel disease (Owens et al., 2004). In vitro functional studies of K464N exhibited lowered efficiency during heterodimer formation, resulting in abnormal filament assembly and an increase in short fragments compared to wild type protein (Owens et al., 2004). K464N was also shown to severely affect the barrier function of a colonocyte monolayer, altering permeability, growth rate, and resistance to heat-stress (Zupancic et al., 2014). The K464N variant is observed in 25/123730 (0.02%) alleles from individuals of non-Finnish European background in large population cohorts (Lek et al., 2016). The K464N variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on the frequency of this variant in large population cohorts, we now interpret K464N as a variant of uncertain significance. -
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not specified Uncertain:1
Variant summary: KRT8 c.1392G>T (p.Lys464Asn) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 237292 control chromosomes (gnomAD). c.1392G>T has been reported in the literature in the heterozygous state in an individual affected with ulcerative colitis who had a family history of inflammatory bowel disease (Owens_2004). This report does not provide unequivocal conclusions about association of the variant with KRT8-Related Disorders. At least two publications report experimental evidence evaluating an impact on protein function (e.g. Owens_2004, Zupancic_2014). The variant exhibited a mildly reduced filament assembly efficiency compared to the WT protein and showed increased permeability in colon cell culture. However, at this time these findings do not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 15090596, 24915158). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at