NM_000455.5:c.112C>A

Variant names:

• chr19-1207025-C-A
• rs1060499954
• NM_000455.5:c.112C>A

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 (★).

• 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 rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.112C>A	p.Pro38Thr	missense_variant	Exon 1 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.112C>A	p.Pro38Thr	missense_variant	Exon 1 of 9		NP_001394184.1
STK11	NR_176325.1	n.1248C>A		non_coding_transcript_exon_variant	Exon 1 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.112C>A	p.Pro38Thr	missense_variant	Exon 1 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.112C>A	p.Pro38Thr	missense_variant	Exon 1 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.-82-11392C>A		intron_variant	Intron 3 of 11	3		ENSP00000477641.2
STK11	ENST00000593219.5	n.112C>A		non_coding_transcript_exon_variant	Exon 1 of 4	3		ENSP00000466610.1

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

Nov 16, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. 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. -

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
MutationAssessor	Uncertain	2.1	.;M;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-1.8	.;N;.
REVEL	Uncertain	0.52
Sift	Benign	0.23	.;T;.
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;