19-1220618-C-G

Position:

• chr19-1220618-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000455.5(STK11):​c.635C>G​(p.Thr212Ser) 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: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.80

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 4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.635C>G	p.Thr212Ser	missense_variant	5/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.635C>G	p.Thr212Ser	missense_variant	5/9		NP_001394184.1
STK11	NR_176325.1	n.1902C>G		non_coding_transcript_exon_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.635C>G	p.Thr212Ser	missense_variant	5/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.635C>G	p.Thr212Ser	missense_variant	5/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.263C>G	p.Thr88Ser	missense_variant	7/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2018

The p.T212S variant (also known as c.635C>G), located in coding exon 5 of the STK11 gene, results from a C to G substitution at nucleotide position 635. The threonine at codon 212 is replaced by serine, an amino acid with similar properties. Two individuals with renal cell carcinoma were reported to have STK11 p.T212S (called LKB1 p.T212S) (Yalniz Z et al. Tumour Biol., 2014 Dec;35:12361-8). 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	Uncertain	0.51
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.86	D;T
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.33	.;N
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-2.8	.;D
REVEL	Uncertain	0.33
Sift	Benign	0.16	.;T
Sift4G	Benign	0.069	T;T
Polyphen		0.16	.;B
Vest4		0.68
MutPred		0.76		Gain of disorder (P = 0.0446);Gain of disorder (P = 0.0446);
MVP		0.74
MPC		2.0
ClinPred		0.93	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.51
gMVP		0.74

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: rs1555738389; hg19: chr19-1220617;