rs1555738475

chr19-1220706-TG-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000455.5(STK11):c.727del(p.Val243SerfsTer44) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G242G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.86

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 18 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
• PP5: Variant 19-1220706-TG-T is Pathogenic according to our data. Variant chr19-1220706-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 446257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1220706-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.727del	p.Val243SerfsTer44	frameshift_variant	5/10	ENST00000326873.12
STK11	NM_001407255.1	c.727del	p.Val243SerfsTer44	frameshift_variant	5/9
STK11	NR_176325.1	n.1994del		non_coding_transcript_exon_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.727del	p.Val243SerfsTer44	frameshift_variant	5/10	1	NM_000455.5	P1

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

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 17, 2018	This variant has not been reported in the literature in individuals with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 446257). For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in STK11 are known to be pathogenic (PMID: 15188174, 16287113). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Val243Serfs*44) in the STK11 gene. It is expected to result in an absent or disrupted protein product. -
Pathogenic, criteria provided, single submitter	clinical testing	National Molecular Genetics Centre of Cancer Research, N.N. Alexandrov National Cancer Centre of Belarus	Aug 07, 2017	Emory Genetics Laboratory Classification Definitions Pathogenic: a. Variants predicted to result in the loss of protein function in a gene for which this is a known mechanism of disease (may or may not have been previously reported in patients with disease) 1. frameshift (an insertion or deletion that is not a multiple of 3 nucleotides). -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1555738475; hg19: chr19-1220705;