19-1223056-G-T

Variant names:

• chr19-1223056-G-T
• rs371264852
• NM_000455.5:c.992G>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_000455.5(STK11):​c.992G>T​(p.Arg331Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000413 in 1,451,908 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R331W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.25
• Publications: 13 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 -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 6 AD,Unknown 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.992G>T	p.Arg331Leu	missense	Exon 8 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.992G>T	p.Arg331Leu	missense	Exon 8 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.2259G>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.992G>T	p.Arg331Leu	missense	Exon 8 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.992G>T	p.Arg331Leu	missense	Exon 8 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.620G>T	p.Arg207Leu	missense	Exon 10 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000413 AC: 6 AN: 1451908 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 721394

African (AFR) AF: 0.00 AC: 0 AN: 33300

American (AMR) AF: 0.00 AC: 0 AN: 43596

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25890

East Asian (EAS) AF: 0.00 AC: 0 AN: 39288

South Asian (SAS) AF: 0.00 AC: 0 AN: 84516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00000541 AC: 6 AN: 1108108

Other (OTH) AF: 0.00 AC: 0 AN: 60028

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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	0.086
BayesDel_addAF	Uncertain	0.013	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.40	N
LIST_S2	Uncertain	0.95	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	2.0	M
PhyloP100		3.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.28
Sift	Benign	0.11	T
Sift4G	Benign	0.17	T
Polyphen		0.0090	B
Vest4		0.67
MutPred		0.45		Loss of disorder (P = 0.0325)
MVP		0.70
MPC		0.048
ClinPred		0.75	D
GERP RS		2.7
PromoterAI		-0.0051	Neutral
Varity_R		0.41
gMVP		0.46
Mutation Taster		=84/16	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: rs371264852; hg19: chr19-1223055;