19-1223169-C-T

Variant names:

• chr19-1223169-C-T
• rs758887235
• NM_000455.5:c.1105C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000455.5(STK11):​c.1105C>T​(p.Pro369Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P369R) has been classified 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:6
• Conservation: PhyloP100: 7.27
• Publications: 4 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3555585).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	NM_000455.5	MANE Select	c.1105C>T	p.Pro369Ser	missense	Exon 8 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.1105C>T	p.Pro369Ser	missense	Exon 8 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.2372C>T		non_coding_transcript_exon	Exon 9 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.1105C>T	p.Pro369Ser	missense	Exon 8 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.1105C>T	p.Pro369Ser	missense	Exon 8 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.733C>T	p.Pro245Ser	missense	Exon 10 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000414 AC: 1 AN: 241680 AF XY: 0.00000758

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000914

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458204 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 2 AN XY: 725178

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26054

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111118

Other (OTH) AF: 0.00 AC: 0 AN: 60270

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000433 Hom.: 0

ExAC AF: 0.00000831 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Hereditary cancer-predisposing syndrome (3)
-	2	-	Peutz-Jeghers syndrome (2)
-	1	-	Melanoma, cutaneous malignant, susceptibility to, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.064
Eigen_PC	Benign	0.057
FATHMM_MKL	Benign	0.60	D
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.3
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.25	N
REVEL	Uncertain	0.30
Sift	Benign	0.072	T
Sift4G	Benign	0.38	T
Polyphen		0.72	P
Vest4		0.54
MutPred		0.28		Gain of glycosylation at P369 (P = 0.0179)
MVP		0.59
MPC		0.26
ClinPred		0.87	D
GERP RS		3.7
PromoterAI		0.050	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.51
Mutation Taster		=44/56	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: rs758887235; hg19: chr19-1223168; COSMIC: COSV58826247; COSMIC: COSV58826247;