19-1222987-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000455.5(STK11):c.923G>T(p.Trp308Leu) variant causes a missense, splice region 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W308C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

STK11
NM_000455.5 missense, splice_region

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:2

Conservation

PhyloP100: 9.60

Publications

10 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: Pathogenic. The variant received 18 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 41 uncertain in NM_000455.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-1222988-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2736757.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.98

PP5

Variant 19-1222987-G-T is Pathogenic according to our data. Variant chr19-1222987-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 220351.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
STK11	NM_000455.5 link	c.923G>T	p.Trp308Leu	missense_variant, splice_region_variant	Exon 8 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1 link	c.923G>T	p.Trp308Leu	missense_variant, splice_region_variant	Exon 8 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.2190G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
STK11	ENST00000326873.12 link	c.923G>T	p.Trp308Leu	missense_variant, splice_region_variant	Exon 8 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1 link	c.923G>T	p.Trp308Leu	missense_variant, splice_region_variant	Exon 8 of 9			ENSP00000498804.1
STK11	ENST00000585748.3 link	c.551G>T	p.Trp184Leu	missense_variant, splice_region_variant	Exon 10 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6 link	n.*748G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 9 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6 link	n.*748G>T		3_prime_UTR_variant	Exon 9 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.000263

Hom.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome;C1336708:Germ cell tumor of testis;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1;C2931038:Familial pancreatic carcinoma

Pathogenic:1

Nov 07, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Peutz-Jeghers syndrome

Pathogenic:1

Sep 24, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces tryptophan with leucine at codon 308 of the STK11 protein (p.Trp308Leu). The tryptophan residue is highly conserved and there is a small physicochemical difference between tryptophan and leucine. For these reasons, this variant has been classified as Likely Pathogenic. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature as a germline variant. Three different missense substitutions at this codon (p.Trp308Cys, p.Trp308Gly, p.Trp308Ser), ¬†one of which abolished STK11 kinase activity in vitro (PMID: 9837816), have been reported in patients affected with Peutz‚ÄìJeghers syndrome (PMID: 9837816, 24604241, 23415580). These observations suggest that this novel missense substitution at the Trp308 residue may affect protein function, but experiments have not been done to test this possibility.

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.30

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

T;D

Eigen

Pathogenic

0.70

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.96

D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Uncertain

0.16

MutationAssessor

Benign

0.0

.;M

PhyloP100

9.6

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.0

.;D

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;D

Sift4G

Uncertain

0.010

D;D

Vest4

0.81

ClinPred

1.0

GERP RS

3.5

PromoterAI

-0.0069

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.89

Mutation Taster

=0/100

disease causing (ClinVar)

(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