rs1555740086

chr19-1226486-G-Achr19-1226486-G-Cchr19-1226486-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000455.5(STK11):c.1141G>A(p.Gly381Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,458,988 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. G381A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.25

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]

ACMG classification

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=0.2657993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.1141G>A	p.Gly381Arg	missense_variant	9/10	ENST00000326873.12
STK11	NR_176325.1	n.2408G>A		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.1141G>A	p.Gly381Arg	missense_variant	9/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1458988 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725710

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 31, 2023

The p.G381R variant (also known as c.1141G>A), located in coding exon 9 of the STK11 gene, results from a G to A substitution at nucleotide position 1141. The glycine at codon 381 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

May 29, 2023

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. ClinVar contains an entry for this variant (Variation ID: 458016). This variant has not been reported in the literature in individuals affected with STK11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 381 of the STK11 protein (p.Gly381Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T
Eigen	Benign	-0.057
Eigen_PC	Benign	0.053
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.82	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.37	T
Sift4G	Benign	0.28	T;T
Polyphen		0.20	.;B
Vest4		0.40
MutPred		0.26		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.43
MPC		0.058
ClinPred		0.48	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.095
gMVP		0.37

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

Other links and lift over

dbSNP: rs1555740086; hg19: chr19-1226485;