19-1219388-C-G

Variant names:

• chr19-1219388-C-G
• rs748464757
• NM_000455.5:c.439C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000455.5(STK11):​c.439C>G​(p.Arg147Gly) variant causes a missense change. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R147C) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 34)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.51
• Publications: 0 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 44 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 chr19-1219389-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3600330.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

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.439C>G	p.Arg147Gly	missense	Exon 3 of 10	NP_000446.1
	STK11	NM_001407255.1		c.439C>G	p.Arg147Gly	missense	Exon 3 of 9	NP_001394184.1
	STK11	NR_176325.1		n.1706C>G		non_coding_transcript_exon	Exon 4 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.439C>G	p.Arg147Gly	missense	Exon 3 of 10	ENSP00000324856.6
	STK11	ENST00000652231.1		c.439C>G	p.Arg147Gly	missense	Exon 3 of 9	ENSP00000498804.1
	STK11	ENST00000585748.3	TSL:3	c.67C>G	p.Arg23Gly	missense	Exon 5 of 12	ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Peutz-Jeghers syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.81	D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.5
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-4.8	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.095	T
Polyphen		0.93	P
Vest4		0.78
MutPred		0.49		Loss of solvent accessibility (P = 0.0509)
MVP		0.81
MPC		1.5
ClinPred		0.99	D
GERP RS		3.8
Varity_R		0.83
gMVP		0.83
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs748464757; hg19: chr19-1219387;