19-1218484-G-C

Variant names:

• chr19-1218484-G-C
• rs775595174
• NM_000455.5:c.358G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000455.5(STK11):​c.358G>C​(p.Glu120Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,206 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 9.74

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 Likely_pathogenic. Variant got 6 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, 0.861

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.358G>C	p.Glu120Gln	missense_variant	Exon 2 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.358G>C	p.Glu120Gln	missense_variant	Exon 2 of 9		NP_001394184.1
STK11	NR_176325.1	n.1625G>C		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.358G>C	p.Glu120Gln	missense_variant	Exon 2 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.358G>C	p.Glu120Gln	missense_variant	Exon 2 of 9			ENSP00000498804.1
STK11	ENST00000585748	c.-15G>C		5_prime_UTR_variant	Exon 4 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.5	n.*183G>C		non_coding_transcript_exon_variant	Exon 3 of 4	3		ENSP00000466610.1
STK11	ENST00000593219.5	n.*183G>C		3_prime_UTR_variant	Exon 3 of 4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249088 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135214

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461206 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726882

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

May 02, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.E120Q variant (also known as c.358G>C), located in coding exon 2 of the STK11 gene, results from a G to C substitution at nucleotide position 358. The glutamic acid at codon 120 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Peutz-Jeghers syndrome Uncertain:1

Sep 27, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 1434313). 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. 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. This variant has not been reported in the literature in individuals affected with STK11-related conditions. This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 120 of the STK11 protein (p.Glu120Gln). This variant is present in population databases (no rsID available, gnomAD 0.003%). -

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

Jan 12, 2024

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	Pathogenic	0.57
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.86	D;D
MetaSVM	Uncertain	0.66	D
MutationAssessor	Benign	1.3	.;L
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.4	.;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.025	.;D
Sift4G	Benign	0.25	T;T
Polyphen		0.86	.;P
Vest4		0.84
MutPred		0.57		Gain of MoRF binding (P = 0.043);Gain of MoRF binding (P = 0.043);
MVP		0.89
MPC		1.8
ClinPred		0.86	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs775595174; hg19: chr19-1218483;