19-1219388-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP3BS1_SupportingBS2

The NM_000455.5(STK11):​c.439C>T​(p.Arg147Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000145 in 1,584,166 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

8
6
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 4.51
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 Likely_benign. Variant got -2 ACMG points.

PM1
In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_000455.5
PP3
MetaRNN computational evidence supports a deleterious effect, 0.785
BS1
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000133 (19/1432494) while in subpopulation SAS AF= 0.0000843 (7/83038). AF 95% confidence interval is 0.0000389. There are 0 homozygotes in gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
STK11NM_000455.5 linkc.439C>T p.Arg147Cys missense_variant 3/10 ENST00000326873.12 NP_000446.1 Q15831-1A0A0S2Z4D1
STK11NM_001407255.1 linkc.439C>T p.Arg147Cys missense_variant 3/9 NP_001394184.1
STK11NR_176325.1 linkn.1706C>T non_coding_transcript_exon_variant 4/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
STK11ENST00000326873.12 linkc.439C>T p.Arg147Cys missense_variant 3/101 NM_000455.5 ENSP00000324856.6 Q15831-1
STK11ENST00000652231.1 linkc.439C>T p.Arg147Cys missense_variant 3/9 ENSP00000498804.1 Q15831-2
STK11ENST00000585748.3 linkc.67C>T p.Arg23Cys missense_variant 5/123 ENSP00000477641.2 A0A087WT72
STK11ENST00000593219.5 linkn.*264C>T downstream_gene_variant 3 ENSP00000466610.1 K7EMR0

Frequencies

GnomAD3 genomes
AF:
0.0000264
AC:
4
AN:
151672
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000210
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000226
AC:
5
AN:
221264
Hom.:
0
AF XY:
0.00000835
AC XY:
1
AN XY:
119716
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000246
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000101
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000133
AC:
19
AN:
1432494
Hom.:
0
Cov.:
37
AF XY:
0.0000169
AC XY:
12
AN XY:
711024
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000237
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000795
Gnomad4 SAS exome
AF:
0.0000843
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000729
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000264
AC:
4
AN:
151672
Hom.:
0
Cov.:
34
AF XY:
0.0000135
AC XY:
1
AN XY:
74070
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000210
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.0000333
AC:
4

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:8Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:5
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 10, 2024This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 147 of the STK11 protein (p.Arg147Cys). This variant is present in population databases (rs748464757, gnomAD 0.02%). This missense change has been observed in individual(s) with melanoma (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 216431). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STK11 protein function. 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. -
Uncertain significance, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthAug 13, 2024This missense variant replaces arginine with cysteine at codon 147 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/252572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingMyriad Genetics, Inc.Apr 12, 2023This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -
Uncertain significance, criteria provided, single submitterclinical testingCounsylJan 26, 2018- -
Hereditary cancer-predisposing syndrome Uncertain:2Benign:1
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthNov 07, 2022This missense variant replaces arginine with cysteine at codon 147 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/252572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submittercurationSema4, Sema4Sep 11, 2021- -
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsFeb 17, 2023This 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 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxSep 05, 2024In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with melanoma (PMID: 34326862); This variant is associated with the following publications: (PMID: 26979979, 15863673, 32459922, 34326862) -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Benign
-0.061
T
BayesDel_noAF
Uncertain
-0.030
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.32
T;D
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.34
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Pathogenic
0.99
D;D
M_CAP
Pathogenic
0.39
D
MetaRNN
Pathogenic
0.78
D;D
MetaSVM
Uncertain
0.27
D
MutationAssessor
Uncertain
2.2
.;M
PrimateAI
Pathogenic
0.86
D
PROVEAN
Pathogenic
-5.7
.;D
REVEL
Pathogenic
0.66
Sift
Pathogenic
0.0
.;D
Sift4G
Benign
0.074
T;T
Polyphen
1.0
.;D
Vest4
0.73
MutPred
0.54
Loss of disorder (P = 0.0451);Loss of disorder (P = 0.0451);
MVP
0.85
MPC
2.2
ClinPred
0.94
D
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.85
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs748464757; hg19: chr19-1219387; API