19-1219388-C-G

Variant names:

• chr19-1219388-C-G
• rs748464757
• NM_000455.5:c.439C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000455.5(STK11):​c.439C>G​(p.Arg147Gly) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R147C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 44 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1219389-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3600330.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.439C>G	p.Arg147Gly	missense_variant	Exon 3 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.439C>G	p.Arg147Gly	missense_variant	Exon 3 of 9		NP_001394184.1
STK11	NR_176325.1	n.1706C>G		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.439C>G	p.Arg147Gly	missense_variant	Exon 3 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.439C>G	p.Arg147Gly	missense_variant	Exon 3 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.67C>G	p.Arg23Gly	missense_variant	Exon 5 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*264C>G		non_coding_transcript_exon_variant	Exon 4 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*264C>G		3_prime_UTR_variant	Exon 4 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:1

Jan 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 147 of the STK11 protein (p.Arg147Gly). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STK11-related conditions. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STK11 protein function. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;D
Eigen	Benign	0.17
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.2	.;L
PhyloP100		4.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.8	.;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	.;D
Sift4G	Benign	0.095	T;T
Polyphen		0.93	.;P
Vest4		0.78
MutPred		0.49		Loss of solvent accessibility (P = 0.0509);Loss of solvent accessibility (P = 0.0509);
MVP		0.81
MPC		1.5
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.83
gMVP		0.83
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs748464757; hg19: chr19-1219387;