19-1220467-G-T

Position:

• chr19-1220467-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 6P and 2B. PM1 PM2 PM5 BP4_Moderate

The ENST00000326873.12(STK11):​c.559G>T​(p.Gly187Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,772 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G187S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: STK11 ENST00000326873.12 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.532

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 4 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 14 uncertain in ENST00000326873.12
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1220466-CGG-CT is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.21159062).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.559G>T	p.Gly187Cys	missense_variant	4/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.559G>T	p.Gly187Cys	missense_variant	4/9		NP_001394184.1
STK11	NR_176325.1	n.1826G>T		non_coding_transcript_exon_variant	5/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.559G>T	p.Gly187Cys	missense_variant	4/10	1	NM_000455.5	ENSP00000324856	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454772 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 723046

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 10, 2018

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. 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 C15"). This variant has not been reported in the literature in individuals with STK11-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with cysteine at codon 187 of the STK11 protein (p.Gly187Cys). The glycine residue is weakly conserved and there is a large physicochemical difference between glycine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	0.80
DANN	Benign	0.94
DEOGEN2	Benign	0.32	T;T;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.21	N
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.21	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Uncertain	2.0	.;M;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-2.0	.;N;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.012	.;D;.
Sift4G	Uncertain	0.023	D;D;T
Polyphen		0.015	.;B;.
Vest4		0.39
MutPred		0.43		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;
MVP		0.68
MPC		1.1
ClinPred		0.11	T
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.31
gMVP		0.72

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: rs587782032; hg19: chr19-1220466;