rs553975112

Positions:

• chr19-1221203-C-A
• chr19-1221203-C-G
• chr19-1221203-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Moderate PP5_Moderate

The NM_000455.5(STK11):​c.735-10C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.9483
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.593

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. Scorers claiming Benign: dbscSNV1_ADA.
• PP5: Variant 19-1221203-C-A is Pathogenic according to our data. Variant chr19-1221203-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 2138176.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-1221203-C-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.735-10C>A		splice_polypyrimidine_tract_variant, intron_variant		ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.735-10C>A		splice_polypyrimidine_tract_variant, intron_variant			NP_001394184.1
STK11	NR_176325.1	n.2002-10C>A		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.735-10C>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000455.5	ENSP00000324856	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peutz-Jeghers syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 02, 2022

This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 5 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 has been observed in individuals with clinical features of Peutz-Jeghers syndrome (PMID: 15188174, 23718779, 32573125; Invitae). For these reasons, this variant has been classified as Pathogenic. Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 32573125). The resulting mRNA is expected to undergo nonsense-mediated decay. This variant is also known as IVS5-10C>A. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	7.8
DANN	Benign	0.80
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.95
dbscSNV1_RF	Pathogenic	0.85
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: 10

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-1221202;