19-1221962-C-T

Position:

• chr19-1221962-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000455.5(STK11):​c.876C>T​(p.Tyr292Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000557 in 1,562,502 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000054 (0 hom.)
• Consequence: STK11 NM_000455.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.15

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 19-1221962-C-T is Benign according to our data. Variant chr19-1221962-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 182886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1221962-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.15 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000539 (76/1410138) while in subpopulation EAS AF= 0.00124 (45/36404). AF 95% confidence interval is 0.000949. There are 0 homozygotes in gnomad4_exome. There are 31 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• 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.876C>T	p.Tyr292Tyr	synonymous_variant	7/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.876C>T	p.Tyr292Tyr	synonymous_variant	7/9		NP_001394184.1
STK11	NR_176325.1	n.2143C>T		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.876C>T	p.Tyr292Tyr	synonymous_variant	7/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.876C>T	p.Tyr292Tyr	synonymous_variant	7/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.504C>T	p.Tyr168Tyr	synonymous_variant	9/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152246 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000467 AC: 8 AN: 171160 Hom.: 0 AF XY: 0.0000653 AC XY: 6 AN XY: 91824

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000823

Gnomad SAS exome AF: 0.0000849

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000708

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000539 AC: 76 AN: 1410138 Hom.: 0 Cov.: 30 AF XY: 0.0000445 AC XY: 31 AN XY: 696848

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000267

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00124

Gnomad4 SAS exome AF: 0.0000375

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000221

Gnomad4 OTH exome AF: 0.0000513

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152364 Hom.: 0 Cov.: 34 AF XY: 0.0000939 AC XY: 7 AN XY: 74508

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000503 Hom.: 0

Bravo AF: 0.0000302

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Benign:5

Likely benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Apr 13, 2023	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Aug 05, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -

Hereditary cancer-predisposing syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jun 01, 2016	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 16, 2015	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 12, 2021	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 29, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

STK11: BP4, BP7 -

STK11-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 21, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.090
DANN	Benign	0.81
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs148928808; hg19: chr19-1221961;