rs1555734898

Positions:

• chr19-1206971-G-A
• chr19-1206971-G-C
• chr19-1206971-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.58G>A​(p.Val20Met) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,476 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • 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: 4.66

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 (HGNC:):

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=0.33954084).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.58G>A	p.Val20Met	missense_variant	1/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.58G>A	p.Val20Met	missense_variant	1/9		NP_001394184.1
STK11	NR_176325.1	n.1194G>A		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.58G>A	p.Val20Met	missense_variant	1/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.58G>A	p.Val20Met	missense_variant	1/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.-82-11446G>A		intron_variant		3		ENSP00000477641.2
STK11	ENST00000593219.5	n.58G>A		non_coding_transcript_exon_variant	1/4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459476 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725880

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.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 06, 2018

This sequence change replaces valine with methionine at codon 20 of the STK11 protein (p.Val20Met). The valine residue is moderately conserved and there is a small physicochemical difference between valine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with STK11-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2020

The p.V20M variant (also known as c.58G>A), located in coding exon 1 of the STK11 gene, results from a G to A substitution at nucleotide position 58. The valine at codon 20 is replaced by methionine, an amino acid with highly similar 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.088	D
BayesDel_noAF	Benign	-0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T;T;T
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.34	T;T;T
MetaSVM	Uncertain	-0.037	T
MutationAssessor	Benign	0.69	.;N;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.38	.;N;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.029	.;D;.
Sift4G	Benign	0.063	T;T;T
Polyphen		0.97	.;D;.
Vest4		0.19
MutPred		0.32		Gain of disorder (P = 0.0371);Gain of disorder (P = 0.0371);Gain of disorder (P = 0.0371);
MVP		0.69
MPC		1.1
ClinPred		0.73	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.096
gMVP		0.31

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: rs1555734898; hg19: chr19-1206970;