chr19-1221319-C-T

Variant names:

• chr19-1221319-C-T
• rs377208033
• NM_000455.5:c.841C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 4P and 3B. PM1 PM2 BP4_Moderate BP6

The NM_000455.5(STK11):​c.841C>T​(p.Pro281Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,457,404 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P281R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 4.02
• Publications: 6 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.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 40 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21465626).
• BP6: Variant 19-1221319-C-T is Benign according to our data. Variant chr19-1221319-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 458067.

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.841C>T	p.Pro281Ser	missense	Exon 6 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.841C>T	p.Pro281Ser	missense	Exon 6 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.2108C>T		non_coding_transcript_exon	Exon 7 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.841C>T	p.Pro281Ser	missense	Exon 6 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.841C>T	p.Pro281Ser	missense	Exon 6 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.469C>T	p.Pro157Ser	missense	Exon 8 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457404 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724688

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44320

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39608

South Asian (SAS) AF: 0.00 AC: 0 AN: 85644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51970

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

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110396

Other (OTH) AF: 0.00 AC: 0 AN: 60214

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	Peutz-Jeghers syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.87	L
PhyloP100		4.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.044
Sift	Benign	0.79	T
Sift4G	Benign	0.75	T
Polyphen		0.016	B
Vest4		0.52
MutPred		0.36		Loss of catalytic residue at P280 (P = 0.0151)
MVP		0.30
MPC		0.044
ClinPred		0.78	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.21
gMVP		0.51
Mutation Taster		=61/39	polymorphism

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: rs377208033; hg19: chr19-1221318;