chr19-1220718-G-C

Variant names:

• chr19-1220718-G-C
• rs587782018
• NM_000455.5:c.734+1G>C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000455.5(STK11):​c.734+1G>C 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. 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_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.86

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 19-1220718-G-C is Pathogenic according to our data. Variant chr19-1220718-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 428792.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.734+1G>C		splice_donor_variant, intron_variant	Intron 5 of 9	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.734+1G>C		splice_donor_variant, intron_variant	Intron 5 of 8		NP_001394184.1
STK11	NR_176325.1	n.2001+1G>C		splice_donor_variant, intron_variant	Intron 6 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.734+1G>C		splice_donor_variant, intron_variant	Intron 5 of 9	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.734+1G>C		splice_donor_variant, intron_variant	Intron 5 of 8			ENSP00000498804.1
STK11	ENST00000585748.3	c.362+1G>C		splice_donor_variant, intron_variant	Intron 7 of 11	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Pathogenic:1

Dec 23, 2015

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.734+1G>C intronic pathogenic mutation results from a G to C substitution one nucleotide after coding exon 5 of the STK11 gene. Though this exact alteration has not been reported in the literature to our knowledge, a different alteration at the same location, c.734+1G>A (designated as IVS5+1G>A) was identified in a child diagnosed with JPS who had a history of hamartomatous polyps and perioral pigmentation (Olschwang S, J. Med. Genet. 2001 Jun; 38(6):356-60). 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 donor site; however, direct experimental evidence is unavailable. In addition to the clinical data presented in the literature, since alterations that disrupt the canonical splice donor site are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.26
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Uncertain	0.96	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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_DG_spliceai		0.36		Position offset: -19
DS_DL_spliceai		1.0		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs587782018; hg19: chr19-1220717; COSMIC: COSV58826034; COSMIC: COSV58826034;