rs121913324

Variant names:

• chr19-1207022-C-T
• rs121913324
• NM_000455.5:c.109C>T

Your query was ambiguous. Multiple possible variants found:

• chr19-1207022-C-T
• chr19-1207022-C-G

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_000455.5(STK11):​c.109C>T​(p.Gln37*) variant causes a stop gained change. 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 (★★). ClinVar reports functional evidence for this variant: "SCV000580891: "In vivo functional studies demonstrate that this alteration confers tumorigenicity (Dahmani R et al. Oncogene, 2015 Apr;34:2337-46)."". Synonymous variant affecting the same amino acid position (i.e. Q37Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STK11 NM_000455.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.68
• Publications: 34 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000580891: "In vivo functional studies demonstrate that this alteration confers tumorigenicity (Dahmani R et al. Oncogene, 2015 Apr;34:2337-46)."
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1207022-C-T is Pathogenic according to our data. Variant chr19-1207022-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 376334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	NM_000455.5	MANE Select	c.109C>T	p.Gln37*	stop_gained	Exon 1 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.109C>T	p.Gln37*	stop_gained	Exon 1 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.1245C>T		non_coding_transcript_exon	Exon 1 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.109C>T	p.Gln37*	stop_gained	Exon 1 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.109C>T	p.Gln37*	stop_gained	Exon 1 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.-82-11395C>T		intron	N/A	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000438 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Peutz-Jeghers syndrome (3)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	47
DANN	Uncertain	1.0
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		5.7
Vest4		0.89
GERP RS		3.9
PromoterAI		-0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121913324; hg19: chr19-1207021; COSMIC: COSV58819862; COSMIC: COSV58819862;