chr19-1226598-G-T

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

14

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

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
STK11NM_000455.5 linkc.1253G>T p.Cys418Phe missense_variant Exon 9 of 10 ENST00000326873.12 NP_000446.1 Q15831-1A0A0S2Z4D1
STK11NR_176325.1 linkn.2520G>T non_coding_transcript_exon_variant Exon 10 of 11

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STK11ENST00000326873.12 linkc.1253G>T p.Cys418Phe missense_variant Exon 9 of 10 1 NM_000455.5 ENSP00000324856.6 Q15831-1
STK11ENST00000585748.3 linkc.881G>T p.Cys294Phe missense_variant Exon 11 of 12 3 ENSP00000477641.2 A0A087WT72
STK11ENST00000593219.6 linkn.*1078G>T non_coding_transcript_exon_variant Exon 10 of 11 3 ENSP00000466610.1 K7EMR0
STK11ENST00000593219.6 linkn.*1078G>T 3_prime_UTR_variant Exon 10 of 11 3 ENSP00000466610.1 K7EMR0

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1412108
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
698300
African (AFR)
AF:
0.00
AC:
0
AN:
31866
American (AMR)
AF:
0.00
AC:
0
AN:
37508
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25270
East Asian (EAS)
AF:
0.00
AC:
0
AN:
36560
South Asian (SAS)
AF:
0.00
AC:
0
AN:
80400
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
48320
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5218
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1088506
Other (OTH)
AF:
0.00
AC:
0
AN:
58460
GnomAD4 genome
Cov.:
33

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
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
20
DANN
Benign
0.96
DEOGEN2
Benign
0.22
T
Eigen
Benign
-0.63
Eigen_PC
Benign
-0.59
FATHMM_MKL
Benign
0.58
D
LIST_S2
Benign
0.32
T
M_CAP
Benign
0.010
T
MetaRNN
Benign
0.13
T
MetaSVM
Benign
-0.96
T
PhyloP100
2.9
Sift4G
Benign
0.75
T
Vest4
0.19
MVP
0.57
ClinPred
0.19
T
GERP RS
0.45
Varity_R
0.096
Mutation Taster
=81/19
polymorphism

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

Other links and lift over

dbSNP: rs878853986; hg19: chr19-1226597; API