chr19-1223055-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000455.5(STK11):​c.991C>G​(p.Arg331Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R331W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

STK11
NM_000455.5 missense

Scores

6
13

Clinical Significance

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

Conservation

PhyloP100: 3.04

Publications

6 publications found
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]
STK11 Gene-Disease associations (from GenCC):
  • familial pancreatic carcinoma
    Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
  • Peutz-Jeghers syndrome
    Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
  • familial ovarian cancer
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 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.991C>G p.Arg331Gly missense_variant Exon 8 of 10 ENST00000326873.12 NP_000446.1 Q15831-1A0A0S2Z4D1
STK11NM_001407255.1 linkc.991C>G p.Arg331Gly missense_variant Exon 8 of 9 NP_001394184.1
STK11NR_176325.1 linkn.2258C>G non_coding_transcript_exon_variant Exon 9 of 11

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STK11ENST00000326873.12 linkc.991C>G p.Arg331Gly missense_variant Exon 8 of 10 1 NM_000455.5 ENSP00000324856.6 Q15831-1
STK11ENST00000652231.1 linkc.991C>G p.Arg331Gly missense_variant Exon 8 of 9 ENSP00000498804.1 Q15831-2
STK11ENST00000585748.3 linkc.619C>G p.Arg207Gly missense_variant Exon 10 of 12 3 ENSP00000477641.2 A0A087WT72
STK11ENST00000593219.6 linkn.*816C>G non_coding_transcript_exon_variant Exon 9 of 11 3 ENSP00000466610.1 K7EMR0
STK11ENST00000593219.6 linkn.*816C>G 3_prime_UTR_variant Exon 9 of 11 3 ENSP00000466610.1 K7EMR0

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

Hereditary cancer-predisposing syndrome Uncertain:1
Mar 01, 2022
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The p.R331G variant (also known as c.991C>G), located in coding exon 8 of the STK11 gene, results from a C to G substitution at nucleotide position 991. The arginine at codon 331 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is conserved. 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:1
Jun 13, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with STK11-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 331 of the STK11 protein (p.Arg331Gly). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.092
BayesDel_addAF
Benign
-0.021
T
BayesDel_noAF
Benign
-0.27
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.32
T;D
Eigen
Benign
-0.33
Eigen_PC
Benign
-0.27
FATHMM_MKL
Benign
0.39
N
LIST_S2
Uncertain
0.93
D;D
M_CAP
Uncertain
0.13
D
MetaRNN
Uncertain
0.51
D;D
MetaSVM
Benign
-0.54
T
MutationAssessor
Benign
2.0
.;M
PhyloP100
3.0
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.5
.;N
REVEL
Uncertain
0.30
Sift
Benign
0.20
.;T
Sift4G
Benign
0.25
T;T
Polyphen
0.0
.;B
Vest4
0.64
MutPred
0.42
Loss of phosphorylation at S334 (P = 0.0779);Loss of phosphorylation at S334 (P = 0.0779);
MVP
0.64
MPC
0.052
ClinPred
0.56
D
GERP RS
1.4
PromoterAI
0.031
Neutral
Varity_R
0.32
gMVP
0.40
Mutation Taster
=76/24
polymorphism

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

Other links and lift over

dbSNP: rs876658594; hg19: chr19-1223054; API