19-1226602-C-T
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000455.5(STK11):c.1257C>T(p.Ser419Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000889 in 1,563,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000092 ( 0 hom. )
Consequence
STK11
NM_000455.5 synonymous
NM_000455.5 synonymous
Scores
7
Clinical Significance
Conservation
PhyloP100: -6.36
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 Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_addAF=-0.446869).
BP6
Variant 19-1226602-C-T is Benign according to our data. Variant chr19-1226602-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 182890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1226602-C-T is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-6.36 with no splicing effect.
BS1
Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000921 (130/1411244) while in subpopulation NFE AF= 0.000104 (113/1088068). AF 95% confidence interval is 0.0000877. There are 0 homozygotes in gnomad4_exome. There are 67 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 9 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| STK11 | NM_000455.5 | c.1257C>T | p.Ser419Ser | synonymous_variant | 9/10 | ENST00000326873.12 | NP_000446.1 | |
| STK11 | NR_176325.1 | n.2524C>T | non_coding_transcript_exon_variant | 10/11 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| STK11 | ENST00000326873.12 | c.1257C>T | p.Ser419Ser | synonymous_variant | 9/10 | 1 | NM_000455.5 | ENSP00000324856.6 | ||
| STK11 | ENST00000585748.3 | c.885C>T | p.Ser295Ser | synonymous_variant | 11/12 | 3 | ENSP00000477641.2 |
Frequencies
GnomAD3 genomes 0.0000591 AC: 9AN: 152220Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000675 AC: 11AN: 163006Hom.: 0 AF XY: 0.0000671 AC XY: 6AN XY: 89376
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GnomAD4 exome AF: 0.0000921 AC: 130AN: 1411244Hom.: 0 Cov.: 31 AF XY: 0.0000960 AC XY: 67AN XY: 697782
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GnomAD4 genome 0.0000591 AC: 9AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.0000807 AC XY: 6AN XY: 74368
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary cancer-predisposing syndrome Benign:3
| Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Oct 15, 2021 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 29, 2017 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 07, 2015 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:2
| Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 13, 2017 | Variant summary: The STK11 c.1257C>T (p.Ser419Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been found in a large, broad control population, ExAC in 4/21878 control chromosomes at a frequency of 0.0001828, which is approximately 29 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000063), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. This variant is co-occuring with a pathogenic variant MSH2 c.366+1G>A in an internal specimen. Taken together, this variant is classified as benign. - |
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The STK11 p.Ser419= variant was identified in the literature in 11241 female controls with frequency 0.00009 and was not identified in 12490 male controls and 53 male or 7051 female breast cancer cases (Momozawa 2018). The variant was also identified in dbSNP (ID: rs375328708) as "With Likely benign allele", ClinVar (classified as benign by GeneDx and Integrated Genetics/Laboratory Corporation of America; as likely benign by Invitae, Ambry Genetics and Color), and LOVD 3.0 (1x as benign) . The variant was also identified with co-occuring pathogenic variant (MSH2 c.366+1G>A) in an internal specimen in Integrated Genetics/Laboratory Corporation of America. The variant was identified in control databases in 13 of 189044 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 16152 chromosomes (freq: 0.00006), Latino in 2 of 25934 chromosomes (freq: 0.00008), European in 8 of 78198 chromosomes (freq: 0.0001), East Asian in 1 of 12748 chromosomes (freq: 0.00008), Finnish in 1 of 18938 chromosomes (freq: 0.00005), while the variant was not observed in the Other, Ashkenazi Jewish, and South Asian populations. The p.Ser419= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Peutz-Jeghers syndrome Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 31, 2024 | - - |
| Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
not specified Benign:1
| Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 19, 2014 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
STK11-related disorder Benign:1
| Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 13, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
GERP RS
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at