19-1206923-G-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_000455.5(STK11):c.10G>T(p.Val4Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V4A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 5.36

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17315343).

BP6

Variant 19-1206923-G-T is Benign according to our data. Variant chr19-1206923-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 578236.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
STK11	NM_000455.5 link	c.10G>T	p.Val4Leu	missense_variant	Exon 1 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1 link	c.10G>T	p.Val4Leu	missense_variant	Exon 1 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.1146G>T		non_coding_transcript_exon_variant	Exon 1 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
STK11	ENST00000326873.12 link	c.10G>T	p.Val4Leu	missense_variant	Exon 1 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1 link	c.10G>T	p.Val4Leu	missense_variant	Exon 1 of 9			ENSP00000498804.1
STK11	ENST00000593219.6 link	n.10G>T		non_coding_transcript_exon_variant	Exon 1 of 11	3		ENSP00000466610.1
STK11	ENST00000585748.3 link	c.-82-11494G>T		intron_variant	Intron 3 of 11	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1431562

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

709480

African (AFR)

AF:

0.00

AC:

AN:

32820

American (AMR)

AF:

0.00

AC:

AN:

39940

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25572

East Asian (EAS)

AF:

0.00

AC:

AN:

37986

South Asian (SAS)

AF:

0.00

AC:

AN:

82464

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50292

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097484

Other (OTH)

AF:

0.00

AC:

AN:

59286

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome

Uncertain:2

Apr 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 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 disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces valine with leucine at codon 4 of the STK11 protein (p.Val4Leu). The valine residue is weakly conserved and there is a small physicochemical difference between valine and leucine. -

May 30, 2024

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces valine with leucine at codon 4 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Melanoma, cutaneous malignant, susceptibility to, 1

Uncertain:1

Feb 15, 2024

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.18

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.66

T;T;T

M_CAP

Benign

0.031

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

.;N;.

PhyloP100

5.4

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.22

.;N;.

REVEL

Benign

0.15

Sift

Benign

0.19

.;T;.

Sift4G

Benign

0.31

T;T;T

Polyphen

0.0010

.;B;.

Vest4

0.12

MutPred

0.20

Loss of catalytic residue at M1 (P = 0.0391);Loss of catalytic residue at M1 (P = 0.0391);Loss of catalytic residue at M1 (P = 0.0391);

MVP

0.28

MPC

0.96

ClinPred

0.52

GERP RS

2.7

PromoterAI

-0.010

Neutral

(source)

Varity_R

0.067

gMVP

0.23

Mutation Taster

=95/5

polymorphism

(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