rs878853992

Positions:

• chr19-1220707-G-A
• chr19-1220707-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000455.5(STK11):​c.724G>A​(p.Gly242Arg) 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. 13/21 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. G242E) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 15 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 chr19-1220708-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 619728.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=3, Uncertain_significance=1}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant 19-1220707-G-A is Pathogenic according to our data. Variant chr19-1220707-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 569540.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.724G>A	p.Gly242Arg	missense_variant	5/10	ENST00000326873.12
STK11	NM_001407255.1	c.724G>A	p.Gly242Arg	missense_variant	5/9
STK11	NR_176325.1	n.1991G>A		non_coding_transcript_exon_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.724G>A	p.Gly242Arg	missense_variant	5/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 23, 2023

For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Gly242 amino acid residue in STK11. Other variant(s) that disrupt this residue have been observed in individuals with STK11-related conditions (PMID: 11389158, 16707622, 31515776), which suggests that this may be a clinically significant amino acid residue. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STK11 protein function. ClinVar contains an entry for this variant (Variation ID: 569540). This missense change has been observed in individuals with Peutz-Jeghers syndrome (PMID: 31515776; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 242 of the STK11 protein (p.Gly242Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.49	T;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	.;H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.96	D
PROVEAN	Pathogenic	-8.0	.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.99
MutPred		0.97		Loss of catalytic residue at V243 (P = 0.0338);Loss of catalytic residue at V243 (P = 0.0338);
MVP		0.98
MPC		2.3
ClinPred		1.0	D
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

Other links and lift over

dbSNP: rs878853992; hg19: chr19-1220706; COSMIC: COSV58824824; COSMIC: COSV58824824;