19-1207064-A-G

Position:

• chr19-1207064-A-G

Variant summary

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

The NM_000455.5(STK11):​c.151A>G​(p.Met51Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,654 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.00

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.151A>G	p.Met51Val	missense_variant	1/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.151A>G	p.Met51Val	missense_variant	1/9		NP_001394184.1
STK11	NR_176325.1	n.1287A>G		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.151A>G	p.Met51Val	missense_variant	1/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.151A>G	p.Met51Val	missense_variant	1/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.-82-11353A>G		intron_variant		3		ENSP00000477641.2
STK11	ENST00000593219.5	n.151A>G		non_coding_transcript_exon_variant	1/4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461654 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727104

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2015

The p.M51V variant (also known as c.151A>G), located in coding exon 1 of the STK11 gene, results from an A to G substitution at nucleotide position 151. The methionine at codon 51 is replaced by valine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6255 samples (12510 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 110000 alleles tested) in our clinical cohort. 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 p.M51V remains unclear. -

Peutz-Jeghers syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 05, 2019

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 sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with STK11-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 51 of the STK11 protein (p.Met51Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;D;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.076
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Uncertain	0.46	T;T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	-0.47	.;N;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.4	.;D;.
REVEL	Uncertain	0.39
Sift	Uncertain	0.018	.;D;.
Sift4G	Benign	0.11	T;T;T
Polyphen		0.18	.;B;.
Vest4		0.65
MutPred		0.58		Loss of catalytic residue at M51 (P = 0.0749);Loss of catalytic residue at M51 (P = 0.0749);Loss of catalytic residue at M51 (P = 0.0749);
MVP		0.76
MPC		1.2
ClinPred		0.96	D
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs730881986; hg19: chr19-1207063;