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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.396C>A	p.Cys132*	stop_gained	Exon 3 of 10	ENST00000326873.12	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_variant	Exon 4 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.396C>A	p.Cys132*	stop_gained	Exon 3 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.396C>A	p.Cys132*	stop_gained	Exon 3 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.24C>A	p.Cys8*	stop_gained	Exon 5 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*221C>A		non_coding_transcript_exon_variant	Exon 4 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*221C>A		3_prime_UTR_variant	Exon 4 of 11	3		ENSP00000466610.1

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

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Mar 01, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.C132* pathogenic mutation (also known as c.396C>A), located in coding exon 3 of the STK11 gene, results from a C to A substitution at nucleotide position 396. This changes the amino acid from a cysteine to a stop codon within coding exon 3. This variant was reported in multiple individuals with features consistent with Peutz-Jeghers syndrome (Ambry internal data; Olschwang S et al. J. Med. Genet. 2001Jun;38(6):356-60). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

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, 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;