19-1218438-G-T

Variant names:

• chr19-1218438-G-T
• rs780749732
• NM_000455.5:c.312G>T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000455.5(STK11):​c.312G>T​(p.Arg104Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar 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: 1.49

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 Uncertain_significance. Variant got 5 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
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.312G>T	p.Arg104Ser	missense_variant	Exon 2 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.312G>T	p.Arg104Ser	missense_variant	Exon 2 of 9		NP_001394184.1
STK11	NR_176325.1	n.1579G>T		non_coding_transcript_exon_variant	Exon 3 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.312G>T	p.Arg104Ser	missense_variant	Exon 2 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.312G>T	p.Arg104Ser	missense_variant	Exon 2 of 9			ENSP00000498804.1
STK11	ENST00000585748	c.-61G>T		5_prime_UTR_variant	Exon 4 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.5	n.*137G>T		non_coding_transcript_exon_variant	Exon 3 of 4	3		ENSP00000466610.1
STK11	ENST00000593219.5	n.*137G>T		3_prime_UTR_variant	Exon 3 of 4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

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

Jan 15, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.33	T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.080	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-0.055	.;N
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.4	.;N
REVEL	Uncertain	0.59
Sift	Benign	0.25	.;T
Sift4G	Benign	0.25	T;T
Polyphen		0.74	.;P
Vest4		0.86
MutPred		0.52		Loss of MoRF binding (P = 0.0739);Loss of MoRF binding (P = 0.0739);
MVP		0.98
MPC		2.3
ClinPred		0.77	D
GERP RS		0.70
Varity_R		0.59
gMVP		0.81

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: rs780749732; hg19: chr19-1218437;