chr19-1221996-C-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS3 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 (★★). ClinVar reports functional evidence for this variant: "SCV000322048: Published functional studies demonstrate a damaging effect: abnormal cellular localization, aberrant phosphorylation patterns, and loss of kinase activity (Boudeau et al., 2003" and additional evidence is available in ClinVar. 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 20 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000322048: Published functional studies demonstrate a damaging effect: abnormal cellular localization, aberrant phosphorylation patterns, and loss of kinase activity (Boudeau et al., 2003; Nezu et al., 1999); SCV000541172: Experimental studies have shown that this missense change affects STK11 function (PMID: 10441497, 12552571).; SCV000918283: Multiple functional studies, Boudeau_2003 and Nezu_1999, found the variant to cause abnormal cellular localization, aberrant phosphorylation patterns, and loss of kinase activity.; SCV004818936: Functional studies have shown that this variant results in the loss of kinase activity (PMID: 10441497, 12552571).; SCV004931342: Functional studies indicate this variant impacts protein function [PMID: 10441497, 12552571, 15561763].; SCV005417833: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV001348700: Functional studies have shown that this variant results in the loss of kinase activity (PMID: 10441497, 12552571).; SCV002687015: Functional studies have shown that this alteration leads to inability of STK11 to autophosphorylate, to phosphorylate p53, to suppress the growth of melanoma cells, and it limits protein localization to the nucleus (Nezu, 1999; Boudeau, 2003).
• 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;