chr19-1226598-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000455.5(STK11):c.1253G>T(p.Cys418Phe) 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. 12/15 in silico tools predict a benign 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. C418S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.90

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12825629).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.1253G>T	p.Cys418Phe	missense_variant	Exon 9 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NR_176325.1 link	n.2520G>T		non_coding_transcript_exon_variant	Exon 10 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STK11	ENST00000326873.12 link	c.1253G>T	p.Cys418Phe	missense_variant	Exon 9 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000585748.3 link	c.881G>T	p.Cys294Phe	missense_variant	Exon 11 of 12	3		ENSP00000477641.2	A0A087WT72
STK11	ENST00000593219.6 link	n.*1078G>T		non_coding_transcript_exon_variant	Exon 10 of 11	3		ENSP00000466610.1	K7EMR0
STK11	ENST00000593219.6 link	n.*1078G>T		3_prime_UTR_variant	Exon 10 of 11	3		ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1412108

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698300

African (AFR)

AF:

0.00

AC:

AN:

31866

American (AMR)

AF:

0.00

AC:

AN:

37508

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25270

East Asian (EAS)

AF:

0.00

AC:

AN:

36560

South Asian (SAS)

AF:

0.00

AC:

AN:

80400

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5218

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088506

Other (OTH)

AF:

0.00

AC:

AN:

58460

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Mar 07, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces cysteine with phenylalanine at codon 418 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.22

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.32

M_CAP

Benign

0.010

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.96

PhyloP100

2.9

Sift4G

Benign

0.75

Vest4

0.19

MVP

0.57

ClinPred

0.19

GERP RS

0.45

Varity_R

0.096

Mutation Taster

=81/19

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over