19-1220452-C-G

Variant names:

• chr19-1220452-C-G
• rs1057522875
• NM_000455.5:c.544C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000455.5(STK11):​c.544C>G​(p.Leu182Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L182R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.04
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 13 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 28 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.544C>G	p.Leu182Val	missense_variant	Exon 4 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.544C>G	p.Leu182Val	missense_variant	Exon 4 of 9		NP_001394184.1
STK11	NR_176325.1	n.1811C>G		non_coding_transcript_exon_variant	Exon 5 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.544C>G	p.Leu182Val	missense_variant	Exon 4 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.544C>G	p.Leu182Val	missense_variant	Exon 4 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.172C>G	p.Leu58Val	missense_variant	Exon 6 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*369C>G		non_coding_transcript_exon_variant	Exon 5 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*369C>G		3_prime_UTR_variant	Exon 5 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.070	D
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;D;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	-0.43	.;N;.
PhyloP100		4.0
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.8	.;D;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.020	.;D;.
Sift4G	Benign	0.069	T;T;T
Polyphen		0.95	.;P;.
Vest4		0.75
MutPred		0.57		Loss of catalytic residue at L182 (P = 0.0663);Loss of catalytic residue at L182 (P = 0.0663);.;
MVP		0.67
MPC		2.2
ClinPred		0.97	D
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.79
gMVP		0.79
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs1057522875; hg19: chr19-1220451;