19-1219388-C-T

Variant names:

• chr19-1219388-C-T
• rs748464757
• NM_000455.5:c.439C>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1 PP3 BP6 BS1 BS2

The NM_000455.5(STK11):​c.439C>T​(p.Arg147Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000145 in 1,584,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:2
• Conservation: PhyloP100: 4.51

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_benign. Variant got -6 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_000455.5
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.785
• BP6: Variant 19-1219388-C-T is Benign according to our data. Variant chr19-1219388-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 216431.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.0000133 (19/1432494) while in subpopulation SAS AF= 0.0000843 (7/83038). AF 95% confidence interval is 0.0000389. There are 0 homozygotes in gnomad4_exome. There are 12 alleles in male gnomad4_exome subpopulation. Median coverage is 37. This position pass quality control queck.
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.439C>T	p.Arg147Cys	missense_variant	Exon 3 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.439C>T	p.Arg147Cys	missense_variant	Exon 3 of 9		NP_001394184.1
STK11	NR_176325.1	n.1706C>T		non_coding_transcript_exon_variant	Exon 4 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.439C>T	p.Arg147Cys	missense_variant	Exon 3 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.439C>T	p.Arg147Cys	missense_variant	Exon 3 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.67C>T	p.Arg23Cys	missense_variant	Exon 5 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.5	n.*264C>T		downstream_gene_variant		3		ENSP00000466610.1

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151672 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000226 AC: 5 AN: 221264 Hom.: 0 AF XY: 0.00000835 AC XY: 1 AN XY: 119716

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000246

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000133 AC: 19 AN: 1432494 Hom.: 0 Cov.: 37 AF XY: 0.0000169 AC XY: 12 AN XY: 711024

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000237

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000795

Gnomad4 SAS exome AF: 0.0000843

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000729

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151672 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74070

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000189

ExAC AF: 0.0000333 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:4 Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 24, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 13, 2024

All of Us Research Program, National Institutes of Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 147 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/252572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Apr 12, 2023

Myriad Genetics, Inc.

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Hereditary cancer-predisposing syndrome Uncertain:2 Benign:1

Nov 07, 2022

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense variant replaces arginine with cysteine at codon 147 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 6/252572 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Feb 17, 2023

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. -

Sep 11, 2021

Sema4, Sema4

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

- -

not provided Uncertain:1

Sep 05, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in an individual with melanoma (PMID: 34326862); This variant is associated with the following publications: (PMID: 26979979, 15863673, 32459922, 34326862) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.32	T;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.39	D
MetaRNN	Pathogenic	0.78	D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Uncertain	2.2	.;M
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.7	.;D
REVEL	Pathogenic	0.66
Sift	Pathogenic	0.0	.;D
Sift4G	Benign	0.074	T;T
Polyphen		1.0	.;D
Vest4		0.73
MutPred		0.54		Loss of disorder (P = 0.0451);Loss of disorder (P = 0.0451);
MVP		0.85
MPC		2.2
ClinPred		0.94	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.77

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: rs748464757; hg19: chr19-1219387;