NM_000455.5:c.718_721delTCGG

Variant names:

• chr19-1220698-TGGTC-T
• rs587776657
• NM_000455.5:c.718_721delTCGG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_000455.5(STK11):​c.718_721delTCGG​(p.Ser240LeufsTer46) 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 (no stars). Synonymous variant affecting the same amino acid position (i.e. S240S) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• 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 11 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 19-1220698-TGGTC-T is Pathogenic according to our data. Variant chr19-1220698-TGGTC-T is described in ClinVar as [Pathogenic]. Clinvar id is 7441.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.718_721delTCGG	p.Ser240LeufsTer46	frameshift_variant	Exon 5 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.718_721delTCGG	p.Ser240LeufsTer46	frameshift_variant	Exon 5 of 9		NP_001394184.1
STK11	NR_176325.1	n.1985_1988delTCGG		non_coding_transcript_exon_variant	Exon 6 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.718_721delTCGG	p.Ser240LeufsTer46	frameshift_variant	Exon 5 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.718_721delTCGG	p.Ser240LeufsTer46	frameshift_variant	Exon 5 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.346_349delTCGG	p.Ser116LeufsTer46	frameshift_variant	Exon 7 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*543_*546delTCGG		non_coding_transcript_exon_variant	Exon 6 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*543_*546delTCGG		3_prime_UTR_variant	Exon 6 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

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

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:1

Jan 01, 1998

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.9
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs587776657; hg19: chr19-1220697;