19-1226622-G-C

Position:

• chr19-1226622-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000455.5(STK11):​c.1277G>C​(p.Arg426Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000215 in 1,395,300 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.88

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.1277G>C	p.Arg426Pro	missense_variant	9/10	ENST00000326873.12	NP_000446.1
STK11	NR_176325.1	n.2544G>C		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.1277G>C	p.Arg426Pro	missense_variant	9/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000585748.3	c.905G>C	p.Arg302Pro	missense_variant	11/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1395300 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688302

Gnomad4 AFR exome AF: 0.0000319

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.0000126

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Apr 11, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 01, 2022	The p.R426P variant (also known as c.1277G>C), located in coding exon 9 of the STK11 gene, results from a G to C substitution at nucleotide position 1277. The arginine at codon 426 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Peutz-Jeghers syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 14, 2022	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 protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function. ClinVar contains an entry for this variant (Variation ID: 237795). This variant has not been reported in the literature in individuals affected with STK11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 426 of the STK11 protein (p.Arg426Pro). -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.016	T
BayesDel_noAF	Benign	-0.21
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Uncertain	0.62	D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	1.8	.;L
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.4	.;N
REVEL	Benign	0.22
Sift	Uncertain	0.0070	.;D
Sift4G	Benign	0.096	T;T
Polyphen		0.53	.;P
Vest4		0.69
MutPred		0.32		.;Gain of catalytic residue at R426 (P = 0.0502);
MVP		0.50
MPC		0.16
ClinPred		0.83	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.30

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: rs752699287; hg19: chr19-1226621;