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GeneBe

19-1220600-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_000455.5(STK11):c.617C>G(p.Ala206Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A206V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

STK11
NM_000455.5 missense

Scores

1
14

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.68
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 88 pathogenic changes around while only 17 benign (84%) in NM_000455.5
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1355834).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
STK11NM_000455.5 linkuse as main transcriptc.617C>G p.Ala206Gly missense_variant 5/10 ENST00000326873.12
STK11NM_001407255.1 linkuse as main transcriptc.617C>G p.Ala206Gly missense_variant 5/9
STK11NR_176325.1 linkuse as main transcriptn.1884C>G non_coding_transcript_exon_variant 6/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
STK11ENST00000326873.12 linkuse as main transcriptc.617C>G p.Ala206Gly missense_variant 5/101 NM_000455.5 P1Q15831-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthMar 06, 2019- -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 06, 2021The p.A206G variant (also known as c.617C>G), located in coding exon 5 of the STK11 gene, results from a C to G substitution at nucleotide position 617. The alanine at codon 206 is replaced by glycine, an amino acid with similar properties. This alteration was not observed in 7,051 unselected female breast cancer patients and was observed with an allele frequency of 0.00018 in 11,241 female controls of Japanese ancestry. In addition, it was not observed in 53 unselected male breast cancer patients and was observed with an allele frequency of 0.0001 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Peutz-Jeghers syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeMay 02, 2023This 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 replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 206 of the STK11 protein (p.Ala206Gly). ClinVar contains an entry for this variant (Variation ID: 527826). 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. 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) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.095
BayesDel_addAF
Benign
-0.21
T
BayesDel_noAF
Benign
-0.54
Cadd
Benign
13
Dann
Benign
0.46
DEOGEN2
Benign
0.30
T;T;T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.75
D
LIST_S2
Uncertain
0.86
D;D;D
M_CAP
Benign
0.042
D
MetaRNN
Benign
0.14
T;T;T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.46
T
Sift4G
Benign
0.37
T;T;T
Polyphen
0.0
.;B;.
Vest4
0.32
MutPred
0.39
Loss of stability (P = 0.0269);Loss of stability (P = 0.0269);.;
MVP
0.34
MPC
1.0
ClinPred
0.19
T
GERP RS
-0.57
Varity_R
0.12
gMVP
0.47

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.10
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: rs764244639; hg19: chr19-1220599; API