chr19-1226602-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000455.5(STK11):c.1257C>T(p.Ser419Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000889 in 1,563,464 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 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000092 ( 0 hom. )

Consequence

STK11
NM_000455.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -6.36

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_addAF=-0.446869).

BP6

Variant 19-1226602-C-T is Benign according to our data. Variant chr19-1226602-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 182890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-1226602-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-6.36 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0000921 (130/1411244) while in subpopulation NFE AF= 0.000104 (113/1088068). AF 95% confidence interval is 0.0000877. There are 0 homozygotes in gnomad4_exome. There are 67 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.1257C>T	p.Ser419Ser	synonymous_variant	Exon 9 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NR_176325.1 link	n.2524C>T		non_coding_transcript_exon_variant	Exon 10 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12 link	c.1257C>T	p.Ser419Ser	synonymous_variant	Exon 9 of 10	1	NM_000455.5	ENSP00000324856.6		Q15831-1
STK11	ENST00000585748.3 link	c.885C>T	p.Ser295Ser	synonymous_variant	Exon 11 of 12	3		ENSP00000477641.2		A0A087WT72

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000675

AC:

AN:

163006

Hom.:

AF XY:

0.0000671

AC XY:

AN XY:

89376

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000776

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000850

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000122

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000921

AC:

130

AN:

1411244

Hom.:

Cov.:

AF XY:

0.0000960

AC XY:

AN XY:

697782

show subpopulations

Gnomad4 AFR exome

AF:

0.0000629

Gnomad4 AMR exome

AF:

0.0000535

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000548

Gnomad4 SAS exome

AF:

0.0000374

Gnomad4 FIN exome

AF:

0.0000828

Gnomad4 NFE exome

AF:

0.000104

Gnomad4 OTH exome

AF:

0.0000685

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000566

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000259

AC:

ExAC

AF:

0.0000880

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Benign:3

Mar 29, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 07, 2015

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Oct 15, 2021

Sema4, Sema4

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided

Benign:2

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The STK11 p.Ser419= variant was identified in the literature in 11241 female controls with frequency 0.00009 and was not identified in 12490 male controls and 53 male or 7051 female breast cancer cases (Momozawa 2018). The variant was also identified in dbSNP (ID: rs375328708) as "With Likely benign allele", ClinVar (classified as benign by GeneDx and Integrated Genetics/Laboratory Corporation of America; as likely benign by Invitae, Ambry Genetics and Color), and LOVD 3.0 (1x as benign) . The variant was also identified with co-occuring pathogenic variant (MSH2 c.366+1G>A) in an internal specimen in Integrated Genetics/Laboratory Corporation of America. The variant was identified in control databases in 13 of 189044 chromosomes at a frequency of 0.00007 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 1 of 16152 chromosomes (freq: 0.00006), Latino in 2 of 25934 chromosomes (freq: 0.00008), European in 8 of 78198 chromosomes (freq: 0.0001), East Asian in 1 of 12748 chromosomes (freq: 0.00008), Finnish in 1 of 18938 chromosomes (freq: 0.00005), while the variant was not observed in the Other, Ashkenazi Jewish, and South Asian populations. The p.Ser419= 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) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Apr 13, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The STK11 c.1257C>T (p.Ser419Ser) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. 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. The variant of interest has been found in a large, broad control population, ExAC in 4/21878 control chromosomes at a frequency of 0.0001828, which is approximately 29 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. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. This variant is co-occuring with a pathogenic variant MSH2 c.366+1G>A in an internal specimen. Taken together, this variant is classified as benign. -

Peutz-Jeghers syndrome

Benign:2

Jul 15, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 14, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Aug 19, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

STK11-related disorder

Benign:1

Mar 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.29

DANN

Benign

0.95

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.013

GERP RS

-6.6

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over