19-1226595-C-G

Variant names:

• chr19-1226595-C-G
• rs1166243253
• NM_000455.5:c.1250C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000455.5(STK11):​c.1250C>G​(p.Ala417Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A417S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1 O:1
• Conservation: PhyloP100: 3.20
• 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: 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11430591).
• BP6: Variant 19-1226595-C-G is Benign according to our data. Variant chr19-1226595-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 527827.

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.1250C>G	p.Ala417Gly	missense	Exon 9 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NR_176325.1		n.2517C>G		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.1250C>G	p.Ala417Gly	missense	Exon 9 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000585748.3	TSL:3	c.878C>G	p.Ala293Gly	missense	Exon 11 of 12	ENSP00000477641.2	A0A087WT72
	STK11	ENST00000593219.6	TSL:3	n.*1075C>G		non_coding_transcript_exon	Exon 10 of 11	ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	Hereditary cancer-predisposing syndrome (2)
-	2	-	Peutz-Jeghers syndrome (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.064
Eigen_PC	Benign	-0.024
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.4	L
PhyloP100		3.2
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.089
Sift	Benign	0.35	T
Sift4G	Benign	0.40	T
Polyphen		0.0	B
Vest4		0.23
MutPred		0.18		Gain of helix (P = 0.0143)
MVP		0.24
MPC		0.041
ClinPred		0.34	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.044
gMVP		0.27
Mutation Taster		=80/20	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: rs1166243253; hg19: chr19-1226594;