dbSNP rs1555738634: STK11:p.Gly257Glu (chr19-1221248-G-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000455.5(STK11):c.770G>A(p.Gly257Glu) 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. G257A) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.63

Publications

0 publications found

Variant links:

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 Gene-Disease associations (from GenCC):

familial pancreatic carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Peutz-Jeghers syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

STK11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
STK11	NM_000455.5 link	c.770G>A	p.Gly257Glu	missense_variant	Exon 6 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1 link	c.770G>A	p.Gly257Glu	missense_variant	Exon 6 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.2037G>A		non_coding_transcript_exon_variant	Exon 7 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
STK11	ENST00000326873.12 link	c.770G>A	p.Gly257Glu	missense_variant	Exon 6 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1 link	c.770G>A	p.Gly257Glu	missense_variant	Exon 6 of 9			ENSP00000498804.1
STK11	ENST00000585748.3 link	c.398G>A	p.Gly133Glu	missense_variant	Exon 8 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6 link	n.*595G>A		non_coding_transcript_exon_variant	Exon 7 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6 link	n.*595G>A		3_prime_UTR_variant	Exon 7 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Aug 29, 2018

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.G257E variant (also known as c.770G>A), located in coding exon 6 of the STK11 gene, results from a G to A substitution at nucleotide position 770. The glycine at codon 257 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. 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

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.15

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.33

T;D

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

1.3

.;L

PhyloP100

9.6

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.7

.;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.010

.;D

Sift4G

Uncertain

0.023

D;T

Polyphen

1.0

.;D

Vest4

0.93

MutPred

0.68

Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);

MVP

0.77

MPC

2.4

ClinPred

0.99

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.91

Mutation Taster

=17/83

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over