rs1131690950

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000455.5(STK11):c.290+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Consequence

STK11
NM_000455.5 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 9.65

Publications

6 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: Pathogenic. The variant received 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-1207204-G-A is Pathogenic according to our data. Variant chr19-1207204-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 428787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.290+1G>A	splice_donor_variant, intron_variant	Intron 1 of 9	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 link	c.290+1G>A	splice_donor_variant, intron_variant	Intron 1 of 8		NP_001394184.1
STK11	NR_176325.1 link	n.1426+1G>A	splice_donor_variant, intron_variant	Intron 1 of 10

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
STK11	ENST00000326873.12 link	c.290+1G>A	splice_donor_variant, intron_variant	Intron 1 of 9	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 link	c.290+1G>A	splice_donor_variant, intron_variant	Intron 1 of 8			ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3 link	c.-82-11213G>A	intron_variant	Intron 3 of 11	3		ENSP00000477641.2	A0A087WT72
STK11	ENST00000593219.6 link	n.290+1G>A	splice_donor_variant, intron_variant	Intron 1 of 10	3		ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome

Pathogenic:5

Mar 14, 2025

Myriad Genetics, Inc.

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered pathogenic. This variant occurs within a consensus splice junction and is predicted to result in abnormal mRNA splicing of either an out-of-frame exon or an in-frame exon necessary for protein stability and/or normal function. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 30528796, 26607058, 23430953,11389158, 29310834]. -

Nov 24, 2021

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site is associated with altered splicing resulting in unknown protein product impact (Invitae). ClinVar contains an entry for this variant (Variation ID: 428787). Disruption of this splice site has been observed in individuals with clinical features of Peutz-Jeghers syndrome (PMID: 11389158, 16287113, 16707622, 17026623, 19727776, 24652667; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change affects a donor splice site in intron 1 of the STK11 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in STK11 are known to be pathogenic (PMID: 15188174, 16287113). -

Dec 31, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

May 01, 2023

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.290+1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide after coding exon 1 of the STK11 gene. This alteration has been identified in multiple affected individuals fulfilling clinical diagnostic criteria for Peutz-Jeghers syndrome (Aretz S et al. Hum Mutat, 2005 Dec;26:513-9; Chow E et al. Clin Genet, 2006 Nov;70:409-14; Hearle N et al. Clin. Cancer Res., 2006 May;12:3209-15; Olschwang S et al. J Med Genet, 2001 Jun;38:356-60; Scott RJ et al. Clin. Genet., 2002 Oct;62:282-7; Huang Z et al. BMC Gastroenterol, 2015 Nov;15:166). In addition to the clinical data presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

Eigen

Pathogenic

0.87

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.97

PhyloP100

9.6

GERP RS

3.9

PromoterAI

-0.31

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.99

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.92

Position offset: 3

DS_DL_spliceai

0.99

Position offset: -1

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