19-1226619-G-C

Variant names:

• chr19-1226619-G-C
• rs730881992
• NM_000455.5:c.1274G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000455.5(STK11):​c.1274G>C​(p.Arg425Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000716 in 1,395,952 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. R425H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.51
• Publications: 8 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1274G>C	p.Arg425Pro	missense	Exon 9 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NR_176325.1		n.2541G>C		non_coding_transcript_exon	Exon 10 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.1274G>C	p.Arg425Pro	missense	Exon 9 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000585748.3	TSL:3	c.902G>C	p.Arg301Pro	missense	Exon 11 of 12	ENSP00000477641.2	A0A087WT72
	STK11	ENST00000593219.6	TSL:3	n.*1099G>C		non_coding_transcript_exon	Exon 10 of 11	ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00 AC: 0 AN: 146880 AF XY: 0.00

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1395952 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 688762

African (AFR) AF: 0.00 AC: 0 AN: 31320

American (AMR) AF: 0.00 AC: 0 AN: 35632

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25004

East Asian (EAS) AF: 0.00 AC: 0 AN: 35854

South Asian (SAS) AF: 0.00 AC: 0 AN: 79380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4758

European-Non Finnish (NFE) AF: 9.26e-7 AC: 1 AN: 1079672

Other (OTH) AF: 0.00 AC: 0 AN: 57776

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	-	Melanoma, cutaneous malignant, susceptibility to, 1 (1)
-	1	-	not provided (1)
-	1	-	Peutz-Jeghers syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.92	D
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.0012	D
MutationAssessor	Benign	2.0	M
PhyloP100		6.5
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.36
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.019	D
Polyphen		0.97	D
Vest4		0.77
MutPred		0.32		Gain of loop (P = 0.0435)
MVP		0.45
MPC		0.25
ClinPred		0.94	D
GERP RS		4.3
Varity_R		0.60
gMVP		0.46
Mutation Taster		=24/76	disease causing

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: rs730881992; hg19: chr19-1226618; COSMIC: COSV53070493;