chr19-1220372-G-T

Variant names:

• chr19-1220372-G-T
• rs587776658
• NM_000455.5:c.465-1G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_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: Splicing: ADA: 1.000
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.86
• Publications: 1 publications found

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

ACMG classification

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 CliVar as Likely_pathogenic. Clinvar id is 4176615.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1220372-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 4176615.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1220372-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 4176615.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1220372-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 4176615.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1220372-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 4176615.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1220372-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 4176615.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1220372-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 4176615.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1220372-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 4176615.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1220372-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 4176615.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1220372-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 4176615.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1220372-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 4176615.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1220372-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 4176615.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1220372-G-T is described in CliVar as Likely_pathogenic. Clinvar id is 4176615.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1220372-G-T is described in CliVar 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
STK11	NM_000455.5	c.465-1G>T		splice_acceptor_variant, intron_variant	Intron 3 of 9	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.465-1G>T		splice_acceptor_variant, intron_variant	Intron 3 of 8		NP_001394184.1
STK11	NR_176325.1	n.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
STK11	ENST00000326873.12	c.465-1G>T		splice_acceptor_variant, intron_variant	Intron 3 of 9	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.465-1G>T		splice_acceptor_variant, intron_variant	Intron 3 of 8			ENSP00000498804.1
STK11	ENST00000585748.3	c.93-1G>T		splice_acceptor_variant, intron_variant	Intron 5 of 11	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*290-1G>T		splice_acceptor_variant, intron_variant	Intron 4 of 10	3		ENSP00000466610.1

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

Other links and lift over

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