rs587781176

Positions:

• chr19-1219317-G-A
• chr19-1219317-G-C
• chr19-1219317-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000455.5(STK11):​c.375-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000836 in 1,578,544 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000085 (1 hom.)
• Consequence: STK11 NM_000455.5 splice_region, intron
• Scores: Splicing: ADA: 0.0001216
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: -3.20

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 19-1219317-G-A is Benign according to our data. Variant chr19-1219317-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 139330.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=9, Uncertain_significance=1, Benign=2}.
• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.375-7G>A		splice_region_variant, intron_variant		ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.375-7G>A		splice_region_variant, intron_variant			NP_001394184.1
STK11	NR_176325.1	n.1642-7G>A		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.375-7G>A		splice_region_variant, intron_variant		1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.375-7G>A		splice_region_variant, intron_variant				ENSP00000498804.1
STK11	ENST00000585748.3	c.3-7G>A		splice_region_variant, intron_variant		3		ENSP00000477641.2
STK11	ENST00000593219.5	n.*200-7G>A		splice_region_variant, intron_variant		3		ENSP00000466610.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152200 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000813 AC: 16 AN: 196718 Hom.: 1 AF XY: 0.000104 AC XY: 11 AN XY: 105706

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000104

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000704

Gnomad SAS exome AF: 0.000161

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000814

Gnomad OTH exome AF: 0.000194

GnomAD4 exome AF: 0.0000848 AC: 121 AN: 1426226 Hom.: 1 Cov.: 36 AF XY: 0.0000878 AC XY: 62 AN XY: 706238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000151

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000265

Gnomad4 SAS exome AF: 0.0000740

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000932

Gnomad4 OTH exome AF: 0.0000846

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152318 Hom.: 0 Cov.: 34 AF XY: 0.0000806 AC XY: 6 AN XY: 74484

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000718

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:1 Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Aug 01, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 14, 2023	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 02, 2017	Variant summary: The STK11 c.375-7G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 4/29158 control chromosomes (1 homozygote) at a frequency of 0.0001372, which is approximately 22 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000063), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likley benign. The variant was reported in one publication in an endometrial cancer patient, without strong evidence for causality (Ring_2016). While the small number of individuals in ExAC with this variant does not allow for the conclusive classification of benign, this variant has been classified as Likely Benign. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Oct 27, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	STK11: BP4, BS1 -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	May 24, 2016	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 05, 2021	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 20, 2014

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.085
DANN	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00012
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

Publications

LitVar

Other links and lift over

dbSNP: rs587781176; hg19: chr19-1219316; COSMIC: COSV58829573; COSMIC: COSV58829573;