rs730881976
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000455.5(STK11):c.719C>A(p.Ser240*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,224 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S240S) has been classified as Benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
STK11
NM_000455.5 stop_gained
NM_000455.5 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 7.80
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-1220702-C-A is Pathogenic according to our data. Variant chr19-1220702-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 216070.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| STK11 | NM_000455.5 | c.719C>A | p.Ser240* | stop_gained | 5/10 | ENST00000326873.12 | NP_000446.1 | |
| STK11 | NM_001407255.1 | c.719C>A | p.Ser240* | stop_gained | 5/9 | NP_001394184.1 | ||
| STK11 | NR_176325.1 | n.1986C>A | non_coding_transcript_exon_variant | 6/11 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| STK11 | ENST00000326873.12 | c.719C>A | p.Ser240* | stop_gained | 5/10 | 1 | NM_000455.5 | ENSP00000324856.6 | ||
| STK11 | ENST00000652231.1 | c.719C>A | p.Ser240* | stop_gained | 5/9 | ENSP00000498804.1 | ||||
| STK11 | ENST00000585748.3 | c.347C>A | p.Ser116* | stop_gained | 7/12 | 3 | ENSP00000477641.2 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457224Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 724674
GnomAD4 exome
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32
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GnomAD4 genome
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Peutz-Jeghers syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 09, 2024 | This sequence change creates a premature translational stop signal (p.Ser240*) in the STK11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STK11 are known to be pathogenic (PMID: 15188174, 16287113). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with clinical features of Peutz-Jeghers syndrome (PMID: 15188174, 17924967; Invitae). ClinVar contains an entry for this variant (Variation ID: 216070). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 09, 2021 | The c.719C>A pathogenic mutation (also known as p.S240*), located in coding exon 5 of the STK11 gene, results from a C to A substitution at nucleotide position 719. This changes the amino acid from a serine to a stop codon within coding exon 5. This mutation has been observed in multiple individuals with a personal and/or family history that is consistent with Peutz-Jeghers syndrome (Lim W et al. Gastroenterology, 2004 Jun;126:1788-94; de Leng WW et al. Clin Genet, 2007 Dec;72:568-73; Aretz S et al. Hum Mutat, 2005 Dec;26:513-9; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration may weaken the native splice donor site and will result in the creation or strengthening of a novel splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -3
DS_DL_spliceai
Position offset: 15
Find out detailed SpliceAI scores and Pangolin per-transcript scores at