19-1220416-C-T

Variant names:

• chr19-1220416-C-T
• rs121913323
• NM_000455.5:c.508C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000455.5(STK11):​c.508C>T​(p.Gln170*) variant causes a stop gained 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. 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, single submitter P:2
• Conservation: PhyloP100: 7.80

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 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 19-1220416-C-T is Pathogenic according to our data. Variant chr19-1220416-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7455.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1220416-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.508C>T	p.Gln170*	stop_gained	Exon 4 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.508C>T	p.Gln170*	stop_gained	Exon 4 of 9		NP_001394184.1
STK11	NR_176325.1	n.1775C>T		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.508C>T	p.Gln170*	stop_gained	Exon 4 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.508C>T	p.Gln170*	stop_gained	Exon 4 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.136C>T	p.Gln46*	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:2

Revision: criteria provided, single submitter

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:1

May 12, 2022

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 (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 7455). This premature translational stop signal has been observed in individual(s) with Peutz-Jeghers syndrome (PMID: 11668633). This sequence change creates a premature translational stop signal (p.Gln170*) in the STK11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in STK11 are known to be pathogenic (PMID: 15188174, 16287113). -

Melanoma, cutaneous malignant, susceptibility to, 1 Pathogenic:1

Mar 04, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.95	D
Vest4		0.98
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121913323; hg19: chr19-1220415; COSMIC: COSV58821403; COSMIC: COSV58821403;