rs56354945

chr19-1207177-C-Achr19-1207177-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000455.5(STK11):c.264C>A(p.Ile88=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00426 in 1,609,288 control chromosomes in the GnomAD database, including 205 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I88I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.021 (109 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (96 hom.)
• Consequence: STK11 NM_000455.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.805

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 Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.26).
• BP6: Variant 19-1207177-C-A is Benign according to our data. Variant chr19-1207177-C-A is described in ClinVar as [Benign]. Clinvar id is 93097.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1207177-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.805 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.264C>A	p.Ile88=	synonymous_variant	1/10	ENST00000326873.12
STK11	NM_001407255.1	c.264C>A	p.Ile88=	synonymous_variant	1/9
STK11	NR_176325.1	n.1400C>A		non_coding_transcript_exon_variant	1/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.264C>A	p.Ile88=	synonymous_variant	1/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes AF: 0.0213 AC: 3234 AN: 152160 Hom.: 108 Cov.: 32

Gnomad AFR AF: 0.0726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.00563 AC: 1330 AN: 236108 Hom.: 39 AF XY: 0.00431 AC XY: 555 AN XY: 128912

Gnomad AFR exome AF: 0.0749

Gnomad AMR exome AF: 0.00556

Gnomad ASJ exome AF: 0.000103

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000135

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000685

Gnomad OTH exome AF: 0.00277

GnomAD4 exome AF: 0.00248 AC: 3614 AN: 1457010 Hom.: 96 Cov.: 31 AF XY: 0.00212 AC XY: 1533 AN XY: 724408

Gnomad4 AFR exome AF: 0.0747

Gnomad4 AMR exome AF: 0.00647

Gnomad4 ASJ exome AF: 0.000116

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000408

Gnomad4 OTH exome AF: 0.00551

GnomAD4 genome AF: 0.0213 AC: 3245 AN: 152278 Hom.: 109 Cov.: 32 AF XY: 0.0205 AC XY: 1527 AN XY: 74440

Gnomad4 AFR AF: 0.0727

Gnomad4 AMR AF: 0.0105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000441

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.00746 Hom.: 18

Bravo AF: 0.0247

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 30, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -

Hereditary cancer-predisposing syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 08, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Nov 18, 2014	This alteration is classified as 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. -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Oct 20, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Jan 03, 2018	- -

Peutz-Jeghers syndrome Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Breast and/or ovarian cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jul 07, 2021

- -

Squamous cell lung carcinoma Benign:1

Likely benign, no assertion criteria provided

clinical testing;in vivo

Faculté Pluridciplinaire Nador, Université Mohamed Premier

May 05, 2020

- -

Malignant tumor of breast Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The STK11 p.Ile88= variant was not identified in the literature nor was it identified in the MutDB, LOVD 3.0, Zhejiang Colon Cancer Database, or Insight Hereditary Tumors Database. The variant was identified in the following databases: dbSNP (ID: rs56354945) as “With other allele”, ClinVar (as likely benign by Illumina and benign by Emory Genetics, Ambry Genetics, PreventionGenetics, and Invitae), Clinvitae (4x), and Cosmic. The variant was identified in control databases in 1969 of 264616 chromosomes (67 homozygous) at a frequency of 0.007441 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Observations by population include African in 1688 (66 homozygous) of 22648 chromosomes (freq: 0.07453), Other in 26 of 6226 chromosomes (freq: 0.004176), Latino in 175 (1 homozygous) of 33114 chromosomes (freq: 0.005285), European (Non-Finnish) in 76 of 120564 chromosomes (freq: 0.00063), and South Asian in 4 of 29712 chromosomes (freq: 0.000135); the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish) populations. The p.Ile88= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.26
Cadd	Benign	11
Dann	Benign	0.92
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs56354945; hg19: chr19-1207176; COSMIC: COSV58820246; COSMIC: COSV58820246;