19-1221961-A-T

Variant names:

• chr19-1221961-A-T
• rs587780011
• NM_000455.5:c.875A>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP4 BS2

The NM_000455.5(STK11):​c.875A>T​(p.Tyr292Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000426 in 1,409,910 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. Y292C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 5.60
• 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 28 uncertain in NM_000455.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.3792882).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

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.875A>T	p.Tyr292Phe	missense	Exon 7 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.875A>T	p.Tyr292Phe	missense	Exon 7 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.2142A>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.875A>T	p.Tyr292Phe	missense	Exon 7 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.875A>T	p.Tyr292Phe	missense	Exon 7 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.503A>T	p.Tyr168Phe	missense	Exon 9 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000117 AC: 2 AN: 170906 AF XY: 0.0000109

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: 0.0000142

Gnomad OTH exome AF: 0.000215

GnomAD4 exome AF: 0.00000426 AC: 6 AN: 1409910 Hom.: 0 Cov.: 30 AF XY: 0.00000287 AC XY: 2 AN XY: 696742

African (AFR) AF: 0.00 AC: 0 AN: 31998

American (AMR) AF: 0.00 AC: 0 AN: 37480

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25332

East Asian (EAS) AF: 0.00 AC: 0 AN: 36402

South Asian (SAS) AF: 0.00 AC: 0 AN: 79946

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00000552 AC: 6 AN: 1086048

Other (OTH) AF: 0.00 AC: 0 AN: 58426

GnomAD4 genome Cov.: 34

Alfa AF: 0.0000434 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	0.0090	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	-0.095	N
PhyloP100		5.6
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.41
Sift	Benign	0.64	T
Sift4G	Benign	0.69	T
Polyphen		0.040	B
Vest4		0.67
MutPred		0.40		Loss of phosphorylation at Y292 (P = 0.0368)
MVP		0.73
MPC		0.060
ClinPred		0.26	T
GERP RS		3.6
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.0
Varity_R		0.28
gMVP		0.61
Mutation Taster		=69/31	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: rs587780011; hg19: chr19-1221960;