chr19-1220595-C-A

Position:

• chr19-1220595-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000455.5(STK11):​c.612C>A​(p.Phe204Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.243

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 mutagenesis_site No effect. Impaired formation of a heterotrimeric complex with STRADA and CAB39; when associated with A-74. (size 0) in uniprot entity STK11_HUMAN
• 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.612C>A	p.Phe204Leu	missense_variant	5/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.612C>A	p.Phe204Leu	missense_variant	5/9		NP_001394184.1
STK11	NR_176325.1	n.1879C>A		non_coding_transcript_exon_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.612C>A	p.Phe204Leu	missense_variant	5/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.612C>A	p.Phe204Leu	missense_variant	5/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.240C>A	p.Phe80Leu	missense_variant	7/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1436042 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 711942

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: 0.00

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 18, 2024	This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 204 of the STK11 protein (p.Phe204Leu). 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. ClinVar contains an entry for this variant (Variation ID: 922825). Invitae Evidence 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 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Mar 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	16
DANN	Uncertain	0.98
DEOGEN2	Benign	0.31	T;D;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.83	.;L;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.9	.;D;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	.;D;.
Sift4G	Uncertain	0.037	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.62
MutPred		0.45		Gain of relative solvent accessibility (P = 0.0479);Gain of relative solvent accessibility (P = 0.0479);.;
MVP		0.55
MPC		2.3
ClinPred		0.99	D
GERP RS		-5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs774100153; hg19: chr19-1220594;