19-1221239-C-T
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong
The NM_000455.5(STK11):c.761C>T(p.Pro254Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P254R) has been classified as Uncertain significance.
Frequency
Consequence
NM_000455.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
STK11 | NM_000455.5 | c.761C>T | p.Pro254Leu | missense_variant | Exon 6 of 10 | ENST00000326873.12 | NP_000446.1 | |
STK11 | NM_001407255.1 | c.761C>T | p.Pro254Leu | missense_variant | Exon 6 of 9 | NP_001394184.1 | ||
STK11 | NR_176325.1 | n.2028C>T | non_coding_transcript_exon_variant | Exon 7 of 11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
STK11 | ENST00000326873.12 | c.761C>T | p.Pro254Leu | missense_variant | Exon 6 of 10 | 1 | NM_000455.5 | ENSP00000324856.6 | ||
STK11 | ENST00000652231.1 | c.761C>T | p.Pro254Leu | missense_variant | Exon 6 of 9 | ENSP00000498804.1 | ||||
STK11 | ENST00000585748.3 | c.389C>T | p.Pro130Leu | missense_variant | Exon 8 of 12 | 3 | ENSP00000477641.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Peutz-Jeghers syndrome Uncertain:1
This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 254 of the STK11 protein (p.Pro254Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STK11-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STK11 protein function with a positive predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.P254L variant (also known as c.761C>T), located in coding exon 6 of the STK11 gene, results from a C to T substitution at nucleotide position 761. The proline at codon 254 is replaced by leucine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
No publications associated with this variant yet.