Genetic Variant STK11:p.Phe255Leu (chr19-1221243-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_000455.5(STK11):c.765C>G(p.Phe255Leu) 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 pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F255V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.115

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_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STK11	NM_000455.5	MANE Select	c.765C>G	p.Phe255Leu	missense	Exon 6 of 10	NP_000446.1
STK11	NM_001407255.1		c.765C>G	p.Phe255Leu	missense	Exon 6 of 9	NP_001394184.1
STK11	NR_176325.1		n.2032C>G		non_coding_transcript_exon	Exon 7 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STK11	ENST00000326873.12	TSL:1 MANE Select	c.765C>G	p.Phe255Leu	missense	Exon 6 of 10	ENSP00000324856.6
STK11	ENST00000652231.1		c.765C>G	p.Phe255Leu	missense	Exon 6 of 9	ENSP00000498804.1
STK11	ENST00000585748.3	TSL:3	c.393C>G	p.Phe131Leu	missense	Exon 8 of 12	ENSP00000477641.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.32

BayesDel_noAF

Pathogenic

0.23

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Benign

0.014

Eigen_PC

Benign

-0.19

FATHMM_MKL

Benign

0.64

LIST_S2

Uncertain

0.91

M_CAP

Pathogenic

0.57

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.6

PhyloP100

-0.12

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-5.4

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.049

Polyphen

1.0

Vest4

0.95

MutPred

0.90

Gain of catalytic residue at F255 (P = 0.0184)

MVP

0.93

MPC

1.6

ClinPred

1.0

GERP RS

-2.0

Varity_R

0.95

gMVP

0.96

Mutation Taster

=13/87

disease causing

(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