19-1221996-C-T

Variant names:

• chr19-1221996-C-T
• rs786201090
• NM_000455.5:c.910C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000455.5(STK11):​c.910C>T​(p.Arg304Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R304Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11 U:1 O:1
• Conservation: PhyloP100: 0.219
• Publications: 24 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: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 34 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1221997-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 428783.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.934
• PP5: Variant 19-1221996-C-T is Pathogenic according to our data. Variant chr19-1221996-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 183802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.910C>T	p.Arg304Trp	missense	Exon 7 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.910C>T	p.Arg304Trp	missense	Exon 7 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.2177C>T		non_coding_transcript_exon	Exon 8 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.910C>T	p.Arg304Trp	missense	Exon 7 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.910C>T	p.Arg304Trp	missense	Exon 7 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.538C>T	p.Arg180Trp	missense	Exon 9 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1418606 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 701954

African (AFR) AF: 0.00 AC: 0 AN: 32314

American (AMR) AF: 0.00 AC: 0 AN: 38786

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25418

East Asian (EAS) AF: 0.00 AC: 0 AN: 36926

South Asian (SAS) AF: 0.00 AC: 0 AN: 80720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49024

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5722

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1090964

Other (OTH) AF: 0.00 AC: 0 AN: 58732

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000233 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Peutz-Jeghers syndrome (6)
3	1	-	not provided (4)
2	-	-	Hereditary cancer-predisposing syndrome (2)
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	0.11
Eigen_PC	Benign	-0.036
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Uncertain	0.11	D
MutationAssessor	Benign	1.5	L
PhyloP100		0.22
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.74
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.77
MutPred		0.85		Loss of disorder (P = 0.0064)
MVP		0.95
MPC		0.30
ClinPred		0.95	D
GERP RS		-2.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.88
Mutation Taster		=11/89	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs786201090; hg19: chr19-1221995; COSMIC: COSV58820334; COSMIC: COSV58820334;