rs1555734959

chr19-1207035-A-Cchr19-1207035-A-Gchr19-1207035-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000455.5(STK11):c.122A>C(p.Lys41Thr) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K41N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.82

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.122A>C	p.Lys41Thr	missense_variant	1/10	ENST00000326873.12
STK11	NM_001407255.1	c.122A>C	p.Lys41Thr	missense_variant	1/9
STK11	NR_176325.1	n.1258A>C		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.122A>C	p.Lys41Thr	missense_variant	1/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

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

Invitae

May 09, 2017

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. 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 disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an STK11-related disease. This sequence change replaces lysine with threonine at codon 41 of the STK11 protein (p.Lys41Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Pathogenic	32
Dann	Uncertain	1.0
DEOGEN2	Benign	0.40	T;D;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	0.44	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.045	D;D;T
Polyphen		0.95	.;P;.
Vest4		0.62
MutPred		0.40		Loss of methylation at K41 (P = 0.0151);Loss of methylation at K41 (P = 0.0151);Loss of methylation at K41 (P = 0.0151);
MVP		0.85
MPC		2.3
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.43
gMVP		0.81

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: rs1555734959; hg19: chr19-1207034;