19-1219412-G-C

Variant names:

• chr19-1219412-G-C
• rs763353991
• NM_000455.5:c.463G>C

Variant summary

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

The NM_000455.5(STK11):​c.463G>C​(p.Gly155Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G155E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: STK11 NM_000455.5 missense, splice_region
• Scores: Splicing: ADA: 0.002764
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.70

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 hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 15 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.463G>C	p.Gly155Arg	missense_variant, splice_region_variant	Exon 3 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.463G>C	p.Gly155Arg	missense_variant, splice_region_variant	Exon 3 of 9		NP_001394184.1
STK11	NR_176325.1	n.1730G>C		splice_region_variant, 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.463G>C	p.Gly155Arg	missense_variant, splice_region_variant	Exon 3 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.463G>C	p.Gly155Arg	missense_variant, splice_region_variant	Exon 3 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.91G>C	p.Gly31Arg	missense_variant, splice_region_variant	Exon 5 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.5	n.*288G>C		downstream_gene_variant		3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:1

Oct 12, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine with arginine at codon 155 of the STK11 protein (p.Gly155Arg). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 582534). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C25"). 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. -

Melanoma, cutaneous malignant, susceptibility to, 1 Uncertain:1

Jun 16, 2023

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.31	T;T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.0052
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.17	.;N
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.1	.;N
REVEL	Uncertain	0.38
Sift	Benign	0.45	.;T
Sift4G	Benign	0.58	T;T
Polyphen		0.64	.;P
Vest4		0.94
MutPred		0.53		Loss of catalytic residue at C158 (P = 0.0867);Loss of catalytic residue at C158 (P = 0.0867);
MVP		0.66
MPC		1.2
ClinPred		0.91	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0028
dbscSNV1_RF	Benign	0.066
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: rs763353991; hg19: chr19-1219411;