rs730881969

Variant names:

• chr19-1219345-C-A
• rs730881969
• NM_000455.5:c.396C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1219345-C-A
• chr19-1219345-C-G
• chr19-1219345-C-T

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.396C>A​(p.Cys132*) variant causes a stop gained change involving the alteration of a non-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 (★). Synonymous variant affecting the same amino acid position (i.e. C132C) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STK11 NM_000455.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.398
• Publications: 6 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 19-1219345-C-A is Pathogenic according to our data. Variant chr19-1219345-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 182895.Status of the report is criteria_provided_single_submitter, 1 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.396C>A	p.Cys132*	stop_gained	Exon 3 of 10	NP_000446.1
	STK11	NM_001407255.1		c.396C>A	p.Cys132*	stop_gained	Exon 3 of 9	NP_001394184.1
	STK11	NR_176325.1		n.1663C>A		non_coding_transcript_exon	Exon 4 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.396C>A	p.Cys132*	stop_gained	Exon 3 of 10	ENSP00000324856.6
	STK11	ENST00000652231.1		c.396C>A	p.Cys132*	stop_gained	Exon 3 of 9	ENSP00000498804.1
	STK11	ENST00000585748.3	TSL:3	c.24C>A	p.Cys8*	stop_gained	Exon 5 of 12	ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1416720 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 702766

African (AFR) AF: 0.00 AC: 0 AN: 32374

American (AMR) AF: 0.00 AC: 0 AN: 41380

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24764

East Asian (EAS) AF: 0.00 AC: 0 AN: 33380

South Asian (SAS) AF: 0.00 AC: 0 AN: 82284

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5532

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089896

Other (OTH) AF: 0.00 AC: 0 AN: 57948

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000559 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Benign	-0.093
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.36	N
PhyloP100		-0.40
Vest4		0.87
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs730881969; hg19: chr19-1219344; COSMIC: COSV58823949; COSMIC: COSV58823949;