19-1220460-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_StrongBP6_Very_StrongBP7BS2

The NM_000455.5(STK11):​c.552C>T​(p.Leu184=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,607,200 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 (★★). Synonymous variant affecting the same amino acid position (i.e. L184L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

STK11
NM_000455.5 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.309
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -17 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.72).
BP6
Variant 19-1220460-C-T is Benign according to our data. Variant chr19-1220460-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 135923.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.309 with no splicing effect.
BS2
High AC in GnomAdExome4 at 16 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
STK11NM_000455.5 linkuse as main transcriptc.552C>T p.Leu184= synonymous_variant 4/10 ENST00000326873.12
STK11NM_001407255.1 linkuse as main transcriptc.552C>T p.Leu184= synonymous_variant 4/9
STK11NR_176325.1 linkuse as main transcriptn.1819C>T non_coding_transcript_exon_variant 5/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
STK11ENST00000326873.12 linkuse as main transcriptc.552C>T p.Leu184= synonymous_variant 4/101 NM_000455.5 P1Q15831-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152178
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000211
AC:
5
AN:
236904
Hom.:
0
AF XY:
0.0000310
AC XY:
4
AN XY:
128988
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000576
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000374
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000110
AC:
16
AN:
1455022
Hom.:
0
Cov.:
32
AF XY:
0.0000111
AC XY:
8
AN XY:
723212
show subpopulations
Gnomad4 AFR exome
AF:
0.0000300
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000117
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152178
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74328
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000579
Hom.:
0
Bravo
AF:
0.0000227

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:10
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome Benign:3
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Likely benign, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthFeb 05, 2024- -
Likely benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
not specified Benign:2
Likely benign, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalFeb 06, 2024- -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpFeb 16, 2018Variant summary: STK11 c.552C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.3e-05 in 265506 control chromosomes (gnomAD). The observed variant frequency is approximately 3.62 fold of the estimated maximal expected allele frequency for a pathogenic variant in STK11 causing Peutz-Jeghers Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.552C>T in individuals affected with Peutz-Jeghers Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015- -
Benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoMar 22, 2019- -
Hereditary cancer-predisposing syndrome Benign:2
Likely benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthJul 17, 2015- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsMay 22, 2014This 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. -
STK11-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesOct 31, 2019This 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.72
CADD
Benign
1.9
DANN
Benign
0.73
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587780719; hg19: chr19-1220459; API