19-1220596-G-T

Variant names:

• chr19-1220596-G-T
• rs730881981
• NM_000455.5:c.613G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000455.5(STK11):​c.613G>T​(p.Ala205Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A205T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.86
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• familial pancreatic carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Peutz-Jeghers syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 56 pathogenic changes around while only 19 benign (75%) in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32971025).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.613G>T	p.Ala205Ser	missense_variant	Exon 5 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.613G>T	p.Ala205Ser	missense_variant	Exon 5 of 9		NP_001394184.1
STK11	NR_176325.1	n.1880G>T		non_coding_transcript_exon_variant	Exon 6 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.613G>T	p.Ala205Ser	missense_variant	Exon 5 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.613G>T	p.Ala205Ser	missense_variant	Exon 5 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.241G>T	p.Ala81Ser	missense_variant	Exon 7 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*438G>T		non_coding_transcript_exon_variant	Exon 6 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*438G>T		3_prime_UTR_variant	Exon 6 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:1

Nov 19, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with STK11-related conditions. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 205 of the STK11 protein (p.Ala205Ser). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.086	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	22
DANN	Benign	0.89
DEOGEN2	Benign	0.24	T;T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.33	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.095	.;N;.
PhyloP100		9.9
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.83	.;N;.
REVEL	Benign	0.29
Sift	Benign	0.51	.;T;.
Sift4G	Benign	0.54	T;T;T
Polyphen		0.13	.;B;.
Vest4		0.68
MutPred		0.25		Gain of disorder (P = 0.0385);Gain of disorder (P = 0.0385);.;
MVP		0.76
MPC		1.5
ClinPred		0.66	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.70
Mutation Taster		=56/44	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs730881981; hg19: chr19-1220595;