rs587782096
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_000455.5(STK11):c.290+4_290+7del variant causes a splice donor, coding sequence change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,350 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
STK11
NM_000455.5 splice_donor, coding_sequence
NM_000455.5 splice_donor, coding_sequence
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.65
Genes affected
STK11 (HGNC:11389): (serine/threonine kinase 11) The protein encoded by this gene is a serine/threonine kinase that regulates cell polarity and energy metabolism and functions as a tumor suppressor. Mutations in this gene have been associated with the autosomal dominant Peutz-Jeghers syndrome, as well as with skin, pancreatic, and testicular cancers. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 1.09447 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.5, offset of 0 (no position change), new splice context is: gaaGTatgg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
STK11 | NM_000455.5 | c.290+4_290+7del | splice_donor_variant, coding_sequence_variant | 1/10 | ENST00000326873.12 | NP_000446.1 | ||
STK11 | NM_001407255.1 | c.290+4_290+7del | splice_donor_variant, coding_sequence_variant | 1/9 | NP_001394184.1 | |||
STK11 | NR_176325.1 | n.1426+4_1426+7del | splice_donor_variant, non_coding_transcript_exon_variant | 1/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
STK11 | ENST00000326873.12 | c.290+4_290+7del | splice_donor_variant, coding_sequence_variant | 1/10 | 1 | NM_000455.5 | ENSP00000324856 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1449350Hom.: 0 AF XY: 0.00000139 AC XY: 1AN XY: 719838
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GnomAD4 genome Cov.: 31
GnomAD4 genome
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31
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Peutz-Jeghers syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 15, 2022 | 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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 141902). This variant has not been reported in the literature in individuals affected with STK11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 1 of the STK11 gene. It does not directly change the encoded amino acid sequence of the STK11 protein. It affects a nucleotide within the consensus splice site. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Feb 25, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 20, 2023 | The c.290+4_290+7delAGTA intronic variant, located in intron 1 of the STK11 gene, results from a deletion of 4 nucleotides within intron 1 of the STK11 gene. The nucleotide positions in this region are generally well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: 6
DS_DL_spliceai
Position offset: 2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at