chr19-1220372-G-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000455.5(STK11):​c.465-1G>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

STK11
NM_000455.5 splice_acceptor, intron

Scores

3
3
1
Splicing: ADA: 1.000
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.86

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: Pathogenic. The variant received 12 ACMG points.

PVS1
Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 5.1, offset of 13, new splice context is: cccgcatgtacttctgtcAGctg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-1220372-G-T is Pathogenic according to our data. Variant chr19-1220372-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4176615.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
STK11NM_000455.5 linkc.465-1G>T splice_acceptor_variant, intron_variant Intron 3 of 9 ENST00000326873.12 NP_000446.1 Q15831-1A0A0S2Z4D1
STK11NM_001407255.1 linkc.465-1G>T splice_acceptor_variant, intron_variant Intron 3 of 8 NP_001394184.1
STK11NR_176325.1 linkn.1732-1G>T splice_acceptor_variant, intron_variant Intron 4 of 10

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
STK11ENST00000326873.12 linkc.465-1G>T splice_acceptor_variant, intron_variant Intron 3 of 9 1 NM_000455.5 ENSP00000324856.6 Q15831-1
STK11ENST00000652231.1 linkc.465-1G>T splice_acceptor_variant, intron_variant Intron 3 of 8 ENSP00000498804.1 Q15831-2
STK11ENST00000585748.3 linkc.93-1G>T splice_acceptor_variant, intron_variant Intron 5 of 11 3 ENSP00000477641.2 A0A087WT72
STK11ENST00000593219.6 linkn.*290-1G>T splice_acceptor_variant, intron_variant Intron 4 of 10 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:
1447710
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
718866
African (AFR)
AF:
0.00
AC:
0
AN:
33296
American (AMR)
AF:
0.00
AC:
0
AN:
42754
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25780
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39186
South Asian (SAS)
AF:
0.00
AC:
0
AN:
83978
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51202
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5750
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1105888
Other (OTH)
AF:
0.00
AC:
0
AN:
59876
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.62
D
BayesDel_noAF
Uncertain
0.0
CADD
Pathogenic
35
DANN
Uncertain
0.99
Eigen
Pathogenic
1.1
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Uncertain
0.96
D
PhyloP100
9.9
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.4
Mutation Taster
=0/100
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.93
Splicevardb
3.0
SpliceAI score (max)
0.99
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.84
Position offset: 14
DS_AL_spliceai
0.99
Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs587776658; hg19: chr19-1220371; COSMIC: COSV58820358; COSMIC: COSV58820358; API