rs587782096

Variant names:

Variant summary

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

The NM_000455.5(STK11):c.290+4_290+7delAGTA variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,449,350 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

STK11
NM_000455.5 splice_region, intron

Scores

Not classified

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 9.65

Publications

1 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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
STK11	NM_000455.5 link	c.290+4_290+7delAGTA	splice_region_variant, intron_variant	Intron 1 of 9	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1 link	c.290+4_290+7delAGTA	splice_region_variant, intron_variant	Intron 1 of 8		NP_001394184.1
STK11	NR_176325.1 link	n.1426+4_1426+7delAGTA	splice_region_variant, intron_variant	Intron 1 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
STK11	ENST00000326873.12 link	c.289_290+2delAAGT	p.Lys97PhefsTer4	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 1 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1 link	c.289_290+2delAAGT	p.Lys97PhefsTer4	frameshift_variant, splice_donor_variant, splice_region_variant, intron_variant	Exon 1 of 9			ENSP00000498804.1
STK11	ENST00000585748.3 link	c.-82-11215_-82-11212delAAGT		intron_variant	Intron 3 of 11	3		ENSP00000477641.2
STK11	ENST00000593219.6 link	n.289_290+2delAAGT		splice_donor_variant, splice_region_variant, intron_variant, non_coding_transcript_exon_variant	Exon 1 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1449350

Hom.:

AF XY:

0.00000139

AC XY:

AN XY:

719838

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33262

American (AMR)

AF:

0.00

AC:

AN:

42374

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25750

East Asian (EAS)

AF:

0.00

AC:

AN:

39212

South Asian (SAS)

AF:

0.00

AC:

AN:

84474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000181

AC:

AN:

1106110

Other (OTH)

AF:

0.00

AC:

AN:

59960

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2

Nov 20, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.290+4_290+7delAGTA intronic variant, located in intron 1 of the STK11 gene, results from a deletion of 4 nucleotides within intron 1 of the STK11 gene. The nucleotide positions in this region are generally well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Feb 25, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Peutz-Jeghers syndrome

Uncertain:2

Jul 15, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 15, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 141902). This sequence change falls in intron 1 of the STK11 gene. It does not directly change the encoded amino acid sequence of the STK11 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STK11-related conditions. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

9.6

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

1.0

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.92

Position offset: 6

DS_DL_spliceai

1.0

Position offset: 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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over