Genetic Variant STK11:p.Arg383Pro (chr19-1226493-G-C) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_000455.5(STK11):c.1148G>C(p.Arg383Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R383H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.65

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

familial pancreatic carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Peutz-Jeghers syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
familial ovarian cancer
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

STK11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13387045).

BP6

Variant 19-1226493-G-C is Benign according to our data. Variant chr19-1226493-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1913842.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	NM_000455.5	MANE Select	c.1148G>C	p.Arg383Pro	missense	Exon 9 of 10	NP_000446.1
	STK11	NR_176325.1		n.2415G>C		non_coding_transcript_exon	Exon 10 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STK11	ENST00000326873.12	TSL:1 MANE Select	c.1148G>C	p.Arg383Pro	missense	Exon 9 of 10	ENSP00000324856.6
STK11	ENST00000585748.3	TSL:3	c.776G>C	p.Arg259Pro	missense	Exon 11 of 12	ENSP00000477641.2
STK11	ENST00000593219.6	TSL:3	n.*973G>C		non_coding_transcript_exon	Exon 10 of 11	ENSP00000466610.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

Peutz-Jeghers syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.26

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.50

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.60

M_CAP

Benign

0.060

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

2.6

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.29

REVEL

Benign

0.034

Sift

Benign

0.21

Sift4G

Benign

0.36

Polyphen

0.016

Vest4

0.27

MutPred

0.37

Loss of sheet (P = 0.0142)

MVP

0.29

MPC

0.053

ClinPred

0.20

GERP RS

2.2

Varity_R

0.14

gMVP

0.31

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over