19-1220700-G-C

Position:

• chr19-1220700-G-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000455.5(STK11):​c.717G>C​(p.Trp239Cys) 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.86

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 19-1220700-G-C is Pathogenic according to our data. Variant chr19-1220700-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 7458.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.717G>C	p.Trp239Cys	missense_variant	5/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.717G>C	p.Trp239Cys	missense_variant	5/9		NP_001394184.1
STK11	NR_176325.1	n.1984G>C		non_coding_transcript_exon_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.717G>C	p.Trp239Cys	missense_variant	5/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.717G>C	p.Trp239Cys	missense_variant	5/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.345G>C	p.Trp115Cys	missense_variant	7/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2016	For these reasons, this variant has been classified as Pathogenic. An experimental study has shown that this missense change impairs the kinase function of STK11 by disrupting association with its binding partners STRAD and MO25 (PMID: 15561763). In addition, multiple PJS-associated missense mutations have been reported in this region, suggesting that this is an important domain for STK11 function (PMID: 20497868, 11389158, 17924967). This variant has been reported in two individuals affected with Peutz-Jeghers syndrome (PJS) (PMID: 12372054, 24054548). ClinVar contains an entry for this variant (Variation ID: 7458). This variant is not present in population databases (rs137853082, ExAC no frequency). This sequence change replaces tryptophan with cysteine at codon 239 of the STK11 protein (p.Trp239Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	.;H
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-13	.;D
REVEL	Pathogenic	0.86
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.99
MutPred		0.92		Loss of ubiquitination at K235 (P = 0.2451);Loss of ubiquitination at K235 (P = 0.2451);
MVP		0.95
MPC		2.6
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
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

Other links and lift over

dbSNP: rs137853082; hg19: chr19-1220699;