chr19-1207003-C-G

Variant summary

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

The NM_000455.5(STK11):​c.90C>G​(p.Asp30Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)

Consequence

STK11
NM_000455.5 missense

Scores

2
10
7

Clinical Significance

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

Conservation

PhyloP100: 3.81
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/exons MANE Protein UniProt
STK11NM_000455.5 linkuse as main transcriptc.90C>G p.Asp30Glu missense_variant 1/10 ENST00000326873.12 NP_000446.1
STK11NM_001407255.1 linkuse as main transcriptc.90C>G p.Asp30Glu missense_variant 1/9 NP_001394184.1
STK11NR_176325.1 linkuse as main transcriptn.1226C>G non_coding_transcript_exon_variant 1/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
STK11ENST00000326873.12 linkuse as main transcriptc.90C>G p.Asp30Glu missense_variant 1/101 NM_000455.5 ENSP00000324856 P1Q15831-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD3 exomes
AF:
0.00000404
AC:
1
AN:
247338
Hom.:
0
AF XY:
0.00000743
AC XY:
1
AN XY:
134642
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000894
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31
ExAC
AF:
0.00000827
AC:
1

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 HealthSep 09, 2020This missense variant replaces aspartic acid with glutamic acid at codon 30 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 1/247338 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 09, 2016The p.D30E variant (also known as c.90C>G), located in coding exon 1 of the STK11 gene, results from a C to G substitution at nucleotide position 90. The aspartic acid at codon 30 is replaced by glutamic acid, 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. In the ESP, this variant was not observed in 6290 samples (12580 alleles) with coverage at this position. 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 this alteration remains unclear. -
Peutz-Jeghers syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 19, 2022In 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 expected to disrupt STK11 protein function. ClinVar contains an entry for this variant (Variation ID: 480723). This variant has not been reported in the literature in individuals affected with STK11-related conditions. This variant is present in population databases (rs771765869, gnomAD 0.0009%). This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 30 of the STK11 protein (p.Asp30Glu). -
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabJul 15, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.92
BayesDel_addAF
Uncertain
0.091
D
BayesDel_noAF
Benign
-0.11
CADD
Benign
23
DANN
Uncertain
1.0
DEOGEN2
Benign
0.35
T;D;T
Eigen
Benign
0.086
Eigen_PC
Benign
0.10
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.92
D;D;D
M_CAP
Uncertain
0.17
D
MetaRNN
Uncertain
0.54
D;D;D
MetaSVM
Uncertain
-0.056
T
MutationAssessor
Uncertain
2.4
.;M;.
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Uncertain
-2.8
.;D;.
REVEL
Uncertain
0.48
Sift
Benign
0.041
.;D;.
Sift4G
Benign
0.064
T;T;T
Polyphen
0.64
.;P;.
Vest4
0.64
MutPred
0.37
Loss of MoRF binding (P = 0.1427);Loss of MoRF binding (P = 0.1427);Loss of MoRF binding (P = 0.1427);
MVP
0.89
MPC
1.1
ClinPred
0.85
D
GERP RS
2.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.7
Varity_R
0.57
gMVP
0.71

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: rs771765869; hg19: chr19-1207002; API