chr19-1220395-G-C

Position:

• chr19-1220395-G-C

Variant summary

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

The ENST00000326873.12(STK11):​c.487G>C​(p.Gly163Arg) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G163D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 ENST00000326873.12 missense
• Clinical Significance: Likely 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]

STK11 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 13 uncertain in ENST00000326873.12
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1220396-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 7448.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 19-1220395-G-C is Pathogenic according to our data. Variant chr19-1220395-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 182898.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.487G>C	p.Gly163Arg	missense_variant	4/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.487G>C	p.Gly163Arg	missense_variant	4/9		NP_001394184.1
STK11	NR_176325.1	n.1754G>C		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.487G>C	p.Gly163Arg	missense_variant	4/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.487G>C	p.Gly163Arg	missense_variant	4/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.115G>C	p.Gly39Arg	missense_variant	6/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2016

The p.G163R variant (also known as c.487G>C), located in coding exon 4 of the STK11 gene, results from a G to C substitution at nucleotide position 487. The glycine at codon 163 is replaced by arginine, an amino acid with dissimilar properties. This variant is in the highly conserved protein kinase domain of the STK11 gene. It has been reported in multiple individuals in different populations with a clinical diagnosis of Peutz-Jeghers syndrome (Barker D et al. Int J Gynecol Pathol. 2010 Jan;29(1):27-32; Fu J, Genet Test Mol Biomarkers 2015 Sep;19(9):528-31). Another alteration at this position, p.G163D, has been reported as a mutation in a patient with Peutz-Jeghers syndrome and was shown to lead to severely impaired but detectable kinase activity (Lim W Gastroenterology. 2004 Jun;126(7):1788-94; Ylikorkala A Hum Mol Genet. 1999 Jan;8(1):45-51). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6328 samples (12656 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.002% (greater than 125000 alleles tested) in our clinical cohort. 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 majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T;D;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	.;H;.
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-8.0	.;D;.
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0010	.;D;.
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.99
MutPred		0.96		Loss of catalytic residue at L164 (P = 0.2929);Loss of catalytic residue at L164 (P = 0.2929);.;
MVP		0.96
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		0.98

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: rs730881972; hg19: chr19-1220394; COSMIC: COSV58830846; COSMIC: COSV58830846;