chr19-1226598-G-A

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>A​(p.Cys418Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,108 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 7.1e-7 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.90

Publications

1 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=0.15578496).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
STK11NM_000455.5 linkc.1253G>A p.Cys418Tyr missense_variant Exon 9 of 10 ENST00000326873.12 NP_000446.1 Q15831-1A0A0S2Z4D1
STK11NR_176325.1 linkn.2520G>A 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>A p.Cys418Tyr missense_variant Exon 9 of 10 1 NM_000455.5 ENSP00000324856.6 Q15831-1
STK11ENST00000585748.3 linkc.881G>A p.Cys294Tyr missense_variant Exon 11 of 12 3 ENSP00000477641.2 A0A087WT72
STK11ENST00000593219.6 linkn.*1078G>A non_coding_transcript_exon_variant Exon 10 of 11 3 ENSP00000466610.1 K7EMR0
STK11ENST00000593219.6 linkn.*1078G>A 3_prime_UTR_variant Exon 10 of 11 3 ENSP00000466610.1 K7EMR0

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
7.08e-7
AC:
1
AN:
1412108
Hom.:
0
Cov.:
31
AF XY:
0.00000143
AC XY:
1
AN XY:
698300
show subpopulations
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:
0.0000274
AC:
1
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
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:1
Jul 26, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 418 of the STK11 protein (p.Cys418Tyr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 657657). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.065
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
20
DANN
Benign
0.95
DEOGEN2
Benign
0.25
T
Eigen
Benign
-0.60
Eigen_PC
Benign
-0.57
FATHMM_MKL
Benign
0.65
D
LIST_S2
Benign
0.39
T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.16
T
MetaSVM
Benign
-0.92
T
PhyloP100
2.9
Sift4G
Benign
0.59
T
Vest4
0.21
MVP
0.60
ClinPred
0.26
T
GERP RS
0.45
Varity_R
0.093
Mutation Taster
=87/13
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