19-1226619-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000455.5(STK11):​c.1274G>C​(p.Arg425Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000716 in 1,395,952 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

15
4

Clinical Significance

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

Conservation

PhyloP100: 6.51
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 Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
STK11NM_000455.5 linkc.1274G>C p.Arg425Pro missense_variant Exon 9 of 10 ENST00000326873.12 NP_000446.1 Q15831-1A0A0S2Z4D1
STK11NR_176325.1 linkn.2541G>C non_coding_transcript_exon_variant Exon 10 of 11

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STK11ENST00000326873.12 linkc.1274G>C p.Arg425Pro missense_variant Exon 9 of 10 1 NM_000455.5 ENSP00000324856.6 Q15831-1
STK11ENST00000585748.3 linkc.902G>C p.Arg301Pro missense_variant Exon 11 of 12 3 ENSP00000477641.2 A0A087WT72

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.16e-7
AC:
1
AN:
1395952
Hom.:
0
Cov.:
31
AF XY:
0.00000145
AC XY:
1
AN XY:
688762
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.26e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Jan 11, 2023
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant has not been reported in the published literature. It also has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Peutz-Jeghers syndrome Uncertain:1
Jul 26, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 425 of the STK11 protein (p.Arg425Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 403784). 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 with a negative predictive value of 95%. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1
Aug 05, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.R425P variant (also known as c.1274G>C), located in coding exon 9 of the STK11 gene, results from a G to C substitution at nucleotide position 1274. The arginine at codon 425 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Melanoma, cutaneous malignant, susceptibility to, 1 Uncertain:1
Mar 01, 2024
Baylor Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.47
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.37
T;D
Eigen
Uncertain
0.68
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.92
D;D
M_CAP
Uncertain
0.26
D
MetaRNN
Uncertain
0.65
D;D
MetaSVM
Uncertain
0.0012
D
MutationAssessor
Benign
2.0
.;M
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-2.0
.;N
REVEL
Uncertain
0.36
Sift
Uncertain
0.0040
.;D
Sift4G
Uncertain
0.019
D;D
Polyphen
0.97
.;D
Vest4
0.77
MutPred
0.32
.;Gain of loop (P = 0.0435);
MVP
0.45
MPC
0.25
ClinPred
0.94
D
GERP RS
4.3
Varity_R
0.60
gMVP
0.46

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: rs730881992; hg19: chr19-1226618; COSMIC: COSV53070493; COSMIC: COSV53070493; API