rs1555738899

Variant names:

• chr19-1222004-CA-TCC
• rs1555738899
• NM_000455.5:c.918_919delCAinsTCC

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.918_919delCAinsTCC​(p.Ser307ProfsTer11) variant causes a frameshift, missense, splice region change. 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. H306H) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: STK11 NM_000455.5 frameshift, missense, splice_region
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.37
• Publications: 0 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: 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 19-1222004-CA-TCC is Pathogenic according to our data. Variant chr19-1222004-CA-TCC is described in ClinVar as [Pathogenic]. Clinvar id is 527812.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.918_919delCAinsTCC	p.Ser307ProfsTer11	frameshift_variant, missense_variant, splice_region_variant	Exon 7 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.918_919delCAinsTCC	p.Ser307ProfsTer11	frameshift_variant, missense_variant, splice_region_variant	Exon 7 of 9		NP_001394184.1
STK11	NR_176325.1	n.2185_2186delCAinsTCC		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.918_919delCAinsTCC	p.Ser307ProfsTer11	frameshift_variant, missense_variant, splice_region_variant	Exon 7 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.918_919delCAinsTCC	p.Ser307ProfsTer11	frameshift_variant, missense_variant, splice_region_variant	Exon 7 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.546_547delCAinsTCC	p.Ser183ProfsTer11	frameshift_variant, missense_variant, splice_region_variant	Exon 9 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*743_*744delCAinsTCC		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*743_*744delCAinsTCC		3_prime_UTR_variant	Exon 8 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 34

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 34

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:1

Sep 20, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Ser307Profs*11) in the STK11 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with STK11-related disease. Loss-of-function variants in STK11 are known to be pathogenic (PMID: 15188174, 16287113). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.4

Splicing

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

Other links and lift over

dbSNP: rs1555738899; hg19: chr19-1222003;