19-1220488-G-T

Position:

chr19-1220488-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000455.5(STK11):c.580G>T(p.Asp194Tyr) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D194E) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.86

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a mutagenesis_site Loss of kinase activity. (size 0) in uniprot entity STK11_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) 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 chr19-1220490-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 19-1220488-G-T is Pathogenic according to our data. Variant chr19-1220488-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 7450.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
STK11	NM_000455.5 linkuse as main transcript	c.580G>T	p.Asp194Tyr	missense_variant	4/10	ENST00000326873.12
STK11	NM_001407255.1 linkuse as main transcript	c.580G>T	p.Asp194Tyr	missense_variant	4/9
STK11	NR_176325.1 linkuse as main transcript	n.1847G>T		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12 linkuse as main transcript	c.580G>T	p.Asp194Tyr	missense_variant	4/10	1	NM_000455.5	P1	Q15831-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1453080

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722078

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2023

Published functional studies demonstrate a damaging effect: reduced kinase activity, increased motility, and loss of tumor suppressor ability (Granado-Martinez et al., 2020; Donnelly et al., 2021); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 15863673, 27467201, 10208439, 26917230, 34849607, 32647375) -

Melanoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 30, 2020

The p.D194Y pathogenic mutation (also known as c.580G>T), located in coding exon 4 of the STK11 gene, results from a G to T substitution at nucleotide position 580. The aspartic acid at codon 194 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration has been reported in an individual with a clinical diagnosis of Peutz-Jeghers syndrome (PJS) (Zheng B et al. J Pediatr Gastroenterol Nutr, 2017 04;64:559-564). Two other alterations at the same codon, p.D194N (c.580G>A) and p.D194E (c.582C>A), have been described in multiple families meeting clinical diagnostic criteria for PJS (Westerman AM et al. Hum. Mutat. 1999;13:476-81; Lim W et al. Br. J. Cancer. 2003 Jul;89:308-13; Schumacher V et al. J. Med. Genet. 2005 May;42:428-35; Hearle NC et al. J. Med. Genet. 2006 Apr;43:e15; Chow E et al. Clin. Genet. 2006 Nov;70:409-14; Klumpen, HJ et al. J Clin Oncol. 2011 Feb 20;29(6):e150-3; Korsse, SE et al. J Med Genet. 2013 Jan;50(1):59-64; Borun P et al. BMC Med. Genet. 2013 May;14:58; Jiang YL et al. Cancer Genet. 2019 01;230:47-57). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). In one functional study, this alteration demonstrated reduced kinase activity compared to wildtype (Granado-Martínez P et al. Commun Biol, 2020 Jul;3:366). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Melanoma, cutaneous malignant, susceptibility to, 1

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 04, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.53

BayesDel_noAF

Pathogenic

0.52

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

T;D;T

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.2

.;H;.

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-9.0

.;D;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

.;D;.

Sift4G

Pathogenic

0.0

D;D;D

Polyphen

1.0

.;D;.

Vest4

1.0

MutPred

0.95

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;

MVP

0.99

MPC

2.4

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

1.0

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over