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GeneBe

rs369033659

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000455.5(STK11):c.1259C>A(p.Ala420Asp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 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. A420S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

STK11
NM_000455.5 missense

Scores

2
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.76
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.26975095).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
STK11NM_000455.5 linkuse as main transcriptc.1259C>A p.Ala420Asp missense_variant 9/10 ENST00000326873.12
STK11NR_176325.1 linkuse as main transcriptn.2526C>A non_coding_transcript_exon_variant 10/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
STK11ENST00000326873.12 linkuse as main transcriptc.1259C>A p.Ala420Asp missense_variant 9/101 NM_000455.5 P1Q15831-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 19, 2020The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. 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. This variant has not been reported in the literature in individuals with STK11-related conditions. This sequence change replaces alanine with aspartic acid at codon 420 of the STK11 protein (p.Ala420Asp). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInstitute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.Dec 08, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.29
BayesDel_addAF
Benign
-0.0049
T
BayesDel_noAF
Benign
-0.24
Cadd
Benign
20
Dann
Uncertain
0.99
DEOGEN2
Benign
0.29
T;T
Eigen
Benign
-0.21
Eigen_PC
Benign
-0.20
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.34
T;D
M_CAP
Benign
0.058
D
MetaRNN
Benign
0.27
T;T
MetaSVM
Benign
-0.76
T
MutationTaster
Benign
1.0
D
PrimateAI
Benign
0.47
T
Sift4G
Benign
0.30
T;T
Polyphen
0.18
.;B
Vest4
0.48
MutPred
0.32
.;Gain of solvent accessibility (P = 0.0354);
MVP
0.49
MPC
0.063
ClinPred
0.58
D
GERP RS
2.2
Varity_R
0.32
gMVP
0.39

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: rs369033659; hg19: chr19-1226603; API