rs1131690951

Variant names:

• chr19-1218501-A-G
• rs1131690951
• NM_000455.5:c.374+1A>G

Your query was ambiguous. Multiple possible variants found:

• chr19-1218501-A-G
• chr19-1218501-A-T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_000455.5(STK11):​c.374+1A>G variant causes a splice donor, intron 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. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 splice_donor, intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.07
• 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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.06451613 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1218501-A-G is Pathogenic according to our data. Variant chr19-1218501-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 428788.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.374+1A>G		splice_donor_variant, intron_variant	Intron 2 of 9	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.374+1A>G		splice_donor_variant, intron_variant	Intron 2 of 8		NP_001394184.1
STK11	NR_176325.1	n.1641+1A>G		splice_donor_variant, intron_variant	Intron 3 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.374+1A>G		splice_donor_variant, intron_variant	Intron 2 of 9	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.374+1A>G		splice_donor_variant, intron_variant	Intron 2 of 8			ENSP00000498804.1
STK11	ENST00000585748.3	c.2+1A>G		splice_donor_variant, intron_variant	Intron 4 of 11	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*199+1A>G		splice_donor_variant, intron_variant	Intron 3 of 10	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:3

Jan 28, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change falls in intron 2 of the STK11 gene. It does not directly change the encoded amino acid sequence of the STK11 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 15608654). ClinVar contains an entry for this variant (Variation ID: 428788). This variant has been observed in individuals with clinical features of Peutz-Jeghers syndrome (PMID: 12112668, 16287113; Invitae). -

May 22, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 10, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.374+1A>G intronic pathogenic mutation results from an A to G substitution one nucleotide after coding exon 2 of the STK11 gene. This mutation has been identified in multiple individuals with Peutz-Jeghers syndrome to date (Resta N, Hum. Mutat. 2002 Jul; 20(1):78-9. Aretz S, Hum. Mutat. 2005 Dec; 26(6):513-9. Mehenni H, Dig. Dis. Sci. 2007 Aug; 52(8):1924-33.). Additionally, RNA analysis has demonstrated that this alteration leads to the use of multiple downstream aberrant 3' splice sites, causing various frameshift transcripts that translationally result in alternate stop codons (Hastings ML, Nat. Struct. Mol. Biol. 2005 Jan; 12(1):54-9.). Based on the available evidence, c.374+1A>G is classified as a pathogenic mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.14
CADD	Uncertain	26
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		9.1
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=2/98	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: rs1131690951; hg19: chr19-1218500; COSMIC: COSV58820569; COSMIC: COSV58820569;