rs1555737463

Positions:

• chr19-1218490-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000455.5(STK11):​c.364A>C​(p.Lys122Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.09

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 5 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.364A>C	p.Lys122Gln	missense_variant	2/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.364A>C	p.Lys122Gln	missense_variant	2/9		NP_001394184.1
STK11	NR_176325.1	n.1631A>C		non_coding_transcript_exon_variant	3/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.364A>C	p.Lys122Gln	missense_variant	2/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.364A>C	p.Lys122Gln	missense_variant	2/9			ENSP00000498804.1
STK11	ENST00000585748	c.-9A>C		5_prime_UTR_variant	4/12	3		ENSP00000477641.2
STK11	ENST00000593219.5	n.*189A>C		non_coding_transcript_exon_variant	3/4	3		ENSP00000466610.1
STK11	ENST00000593219.5	n.*189A>C		3_prime_UTR_variant	3/4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 02, 2017

This variant has not been reported in the literature in individuals with STK11-related disease. 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 do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency). This sequence change replaces lysine with glutamine at codon 122 of the STK11 protein (p.Lys122Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	0.57	.;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-4.0	.;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.010	D;D
Polyphen		1.0	.;D
Vest4		0.74
MutPred		0.43		Loss of methylation at K122 (P = 6e-04);Loss of methylation at K122 (P = 6e-04);
MVP		0.91
MPC		2.2
ClinPred		1.0	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.68

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: rs1555737463; hg19: chr19-1218489;