19-1207169-C-G

Variant names:

• chr19-1207169-C-G
• rs1057520039
• NM_000455.5:c.256C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000455.5(STK11):​c.256C>G​(p.Arg86Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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. R86Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.19
• Publications: 9 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 2 ACMG points.

• 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.256C>G	p.Arg86Gly	missense_variant	Exon 1 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.256C>G	p.Arg86Gly	missense_variant	Exon 1 of 9		NP_001394184.1
STK11	NR_176325.1	n.1392C>G		non_coding_transcript_exon_variant	Exon 1 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.256C>G	p.Arg86Gly	missense_variant	Exon 1 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.256C>G	p.Arg86Gly	missense_variant	Exon 1 of 9			ENSP00000498804.1
STK11	ENST00000593219.6	n.256C>G		non_coding_transcript_exon_variant	Exon 1 of 11	3		ENSP00000466610.1
STK11	ENST00000585748.3	c.-82-11248C>G		intron_variant	Intron 3 of 11	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Squamous cell lung carcinoma Pathogenic:1

May 13, 2016

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;D;T
Eigen	Uncertain	0.26
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Uncertain	0.62	D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.3	.;L;.
PhyloP100		2.2
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-6.2	.;D;.
REVEL	Uncertain	0.52
Sift	Uncertain	0.0010	.;D;.
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.70
MutPred		0.35		Loss of solvent accessibility (P = 0.0053);Loss of solvent accessibility (P = 0.0053);Loss of solvent accessibility (P = 0.0053);
MVP		0.85
MPC		2.4
ClinPred		0.99	D
GERP RS		3.9
PromoterAI		-0.042	Neutral
Varity_R		0.95
gMVP		0.84
Mutation Taster		=37/63	disease causing (ClinVar)

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: rs1057520039; hg19: chr19-1207168; COSMIC: COSV58828526;