19-1223127-G-C

Variant names:

• chr19-1223127-G-C
• rs769403473
• NM_000455.5:c.1063G>C

Variant summary

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

The NM_000455.5(STK11):​c.1063G>C​(p.Asp355His) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,459,526 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. D355N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 6.19
• Publications: 6 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.1063G>C	p.Asp355His	missense	Exon 8 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.1063G>C	p.Asp355His	missense	Exon 8 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.2330G>C		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.1063G>C	p.Asp355His	missense	Exon 8 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.1063G>C	p.Asp355His	missense	Exon 8 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.691G>C	p.Asp231His	missense	Exon 10 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000408 AC: 1 AN: 245024 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000292

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: 0.00000137 AC: 2 AN: 1459526 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 725930

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.0000224 AC: 1 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86014

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111516

Other (OTH) AF: 0.00 AC: 0 AN: 60324

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000660 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	22
DANN	Benign	0.61
DEOGEN2	Benign	0.37	T
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.8	L
PhyloP100		6.2
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.31
Sift	Benign	0.37	T
Sift4G	Benign	0.57	T
Polyphen		0.84	P
Vest4		0.46
MutPred		0.44		Gain of catalytic residue at D359 (P = 0.1091)
MVP		0.70
MPC		0.22
ClinPred		0.32	T
GERP RS		0.48
PromoterAI		-0.033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.096
gMVP		0.33
Mutation Taster		=74/26	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: rs769403473; hg19: chr19-1223126;