rs112675807

Variant names:

• chr19-1218416-G-A
• rs112675807
• NM_000455.5:c.291-1G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1218416-G-A
• chr19-1218416-G-C
• chr19-1218416-G-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.291-1G>A variant causes a splice acceptor, 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 9.73
• Publications: 4 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. Cryptic splice site detected, with MaxEntScore 11, offset of 1, new splice context is: cctgtcctctctgtcccaAGgaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1218416-G-A is Pathogenic according to our data. Variant chr19-1218416-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 821978.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.291-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 9	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.291-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 8		NP_001394184.1
STK11	NR_176325.1	n.1558-1G>A		splice_acceptor_variant, intron_variant	Intron 2 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.291-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 9	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.291-1G>A		splice_acceptor_variant, intron_variant	Intron 1 of 8			ENSP00000498804.1
STK11	ENST00000585748.3	c.-82-1G>A		splice_acceptor_variant, intron_variant	Intron 3 of 11	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*116-1G>A		splice_acceptor_variant, intron_variant	Intron 2 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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial ovarian cancer Pathogenic:1

Nov 08, 2024

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Pathogenic:1

Jul 10, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.291-1G>A intronic pathogenic mutation results from a G to A substitution one nucleotide upstream from coding exon 2 of the STK11 gene. This variant has been reported in one Chinese family with Peutz-Jeghers syndrome (Wang Z et al. Hum. Mutat., 2014 Jul;35:851-8). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	35
DANN	Uncertain	0.99
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
PhyloP100		9.7
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		1.0		Position offset: 2
DS_AL_spliceai		1.0		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs112675807; hg19: chr19-1218415;