19-1226641-G-C

Variant summary

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

The NM_000455.5(STK11):​c.1296G>C​(p.Gln432His) 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. 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. Q432R) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

STK11
NM_000455.5 missense

Scores

1
8
10

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.47

Publications

5 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.1296G>C p.Gln432His missense_variant Exon 9 of 10 ENST00000326873.12 NP_000446.1 Q15831-1A0A0S2Z4D1
STK11NR_176325.1 linkn.2563G>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.1296G>C p.Gln432His missense_variant Exon 9 of 10 1 NM_000455.5 ENSP00000324856.6 Q15831-1
STK11ENST00000585748.3 linkc.924G>C p.Gln308His missense_variant Exon 11 of 12 3 ENSP00000477641.2 A0A087WT72
STK11ENST00000593219.6 linkn.*1121G>C non_coding_transcript_exon_variant Exon 10 of 11 3 ENSP00000466610.1 K7EMR0
STK11ENST00000593219.6 linkn.*1121G>C 3_prime_UTR_variant Exon 10 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:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2
Nov 03, 2015
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Thep.Q432Hvariant (also known as c.1296G>C), located in coding exon 9 of theSTK11gene, results from a G to C substitution at nucleotide position 1296. The glutamine at codon 432 is replaced by histidine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. This position was not covered in the ESP. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 125000 alleles tested) in our clinical cohort. 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 p.Q432H remains unclear.​ -

Apr 23, 2019
Color Diagnostics, LLC DBA Color Health
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Peutz-Jeghers syndrome Uncertain:1
Jul 15, 2021
Genome-Nilou Lab
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
Benign
0.28
BayesDel_addAF
Uncertain
0.035
T
BayesDel_noAF
Benign
-0.19
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.32
T;D
Eigen
Uncertain
0.21
Eigen_PC
Benign
0.15
FATHMM_MKL
Uncertain
0.86
D
LIST_S2
Benign
0.78
T;T
M_CAP
Uncertain
0.15
D
MetaRNN
Benign
0.40
T;T
MetaSVM
Benign
-0.47
T
MutationAssessor
Benign
1.1
.;L
PhyloP100
5.5
PrimateAI
Uncertain
0.73
T
PROVEAN
Benign
-1.2
.;N
REVEL
Uncertain
0.31
Sift
Pathogenic
0.0
.;D
Sift4G
Uncertain
0.012
D;D
Polyphen
0.94
.;P
Vest4
0.56
MutPred
0.26
.;Loss of helix (P = 0.079);
MVP
0.74
MPC
0.23
ClinPred
0.79
D
GERP RS
1.9
Varity_R
0.38
gMVP
0.42
Mutation Taster
=47/53
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.22
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.22
Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs587781179; hg19: chr19-1226640; API