rs1060499954

chr19-1207025-C-Achr19-1207025-C-Gchr19-1207025-C-T

Variant summary

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

The NM_000455.5(STK11):c.112C>A(p.Pro38Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P38A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.48

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.112C>A	p.Pro38Thr	missense_variant	1/10	ENST00000326873.12
STK11	NM_001407255.1	c.112C>A	p.Pro38Thr	missense_variant	1/9
STK11	NR_176325.1	n.1248C>A		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.112C>A	p.Pro38Thr	missense_variant	1/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Nov 16, 2016

This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a STK11-related disease. This sequence change replaces proline with threonine at codon 38 of the STK11 protein (p.Pro38Thr). The proline residue is highly conserved and there is a small physicochemical difference between proline and threonine. 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: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.33	T;D;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Uncertain	-0.022	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
Sift4G	Benign	0.24	T;T;T
Polyphen		0.41	.;B;.
Vest4		0.68
MutPred		0.41		Gain of phosphorylation at P38 (P = 0.0263);Gain of phosphorylation at P38 (P = 0.0263);Gain of phosphorylation at P38 (P = 0.0263);
MVP		0.68
MPC		1.2
ClinPred		0.90	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.31
gMVP		0.87

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: rs1060499954; hg19: chr19-1207024;