Variant chr19-1223080-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000326873.12(STK11):c.1016C>G(p.Pro339Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,609,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P339A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

STK11
ENST00000326873.12 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.60

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.803

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
STK11	NM_000455.5 linkuse as main transcript	c.1016C>G	p.Pro339Arg	missense_variant	8/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1 linkuse as main transcript	c.1016C>G	p.Pro339Arg	missense_variant	8/9		NP_001394184.1
STK11	NR_176325.1 linkuse as main transcript	n.2283C>G		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12 linkuse as main transcript	c.1016C>G	p.Pro339Arg	missense_variant	8/10	1	NM_000455.5	ENSP00000324856	P1	Q15831-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1456910

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724266

show subpopulations

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:

9.01e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152260

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 09, 2016	In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a STK11-related disease. This sequence change replaces proline with arginine at codon 339 of the STK11 protein (p.Pro339Arg). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and arginine. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 14, 2022

The p.P339R variant (also known as c.1016C>G), located in coding exon 8 of the STK11 gene, results from a C to G substitution at nucleotide position 1016. The proline at codon 339 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Melanoma, cutaneous malignant, susceptibility to, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Uncertain

0.050

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;D

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Benign

0.71

LIST_S2

Pathogenic

0.98

D;D

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.80

D;D

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

2.0

.;M

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-6.6

.;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0060

.;D

Sift4G

Uncertain

0.010

D;D

Polyphen

0.98

.;D

Vest4

0.84

MutPred

0.40

Gain of helix (P = 0.005);Gain of helix (P = 0.005);

MVP

0.69

MPC

0.28

ClinPred

0.99

GERP RS

3.8

Varity_R

0.90

gMVP

0.67

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