rs786201349

Variant names:

• chr19-1220376-C-G
• rs786201349
• NM_000455.5:c.468C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-1220376-C-G
• chr19-1220376-C-T

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PVS1 PM2 PP3 PP5_Very_Strong

The NM_000455.5(STK11):​c.468C>G​(p.Tyr156*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 1.76

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]

ACMG classification

Verdict is Pathogenic. Variant got 19 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 19-1220376-C-G is Pathogenic according to our data. Variant chr19-1220376-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 527815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1220376-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.468C>G	p.Tyr156*	stop_gained	Exon 4 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.468C>G	p.Tyr156*	stop_gained	Exon 4 of 9		NP_001394184.1
STK11	NR_176325.1	n.1735C>G		non_coding_transcript_exon_variant	Exon 5 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.468C>G	p.Tyr156*	stop_gained	Exon 4 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.468C>G	p.Tyr156*	stop_gained	Exon 4 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.96C>G	p.Tyr32*	stop_gained	Exon 6 of 12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:3

Feb 11, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: STK11 c.468C>G (p.Tyr156X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant was absent in 220968 control chromosomes (gnomAD). c.468C>G has been reported in the literature in multiple individuals affected with Peutz-Jeghers Syndrome (Schumacher 2005, Korsse 2013). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Feb 15, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Tyr156*) in the STK11 gene. It is expected to result in an absent or disrupted protein product. This variant has been reported in several individuals affected with Peutz-Jeghers syndrome (PMID: 15863673, 23240097, Invitae). Loss-of-function variants in STK11 are known to be pathogenic (PMID: 15188174, 16287113). For these reasons, this variant has been classified as Pathogenic. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	50
DANN	Uncertain	1.0
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.87	D
Vest4		0.96
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.78		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.78		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs786201349; hg19: chr19-1220375;