Genetic Variant STK11:p.Ala417Asp (chr19-1226595-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000455.5(STK11):c.1250C>A(p.Ala417Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,350 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A417G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 3.20

Publications

0 publications found

Variant links:

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

STK11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25036538).

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>A	p.Ala417Asp	missense	Exon 9 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NR_176325.1		n.2517C>A		non_coding_transcript_exon	Exon 10 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STK11	ENST00000326873.12	TSL:1 MANE Select	c.1250C>A	p.Ala417Asp	missense	Exon 9 of 10	ENSP00000324856.6	Q15831-1
STK11	ENST00000585748.3	TSL:3	c.878C>A	p.Ala293Asp	missense	Exon 11 of 12	ENSP00000477641.2	A0A087WT72
STK11	ENST00000593219.6	TSL:3	n.*1075C>A		non_coding_transcript_exon	Exon 10 of 11	ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.07e-7

AC:

AN:

1414350

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699574

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31994

American (AMR)

AF:

0.00

AC:

AN:

37894

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25300

East Asian (EAS)

AF:

0.00

AC:

AN:

36700

South Asian (SAS)

AF:

0.00

AC:

AN:

80632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48516

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5258

European-Non Finnish (NFE)

AF:

9.18e-7

AC:

AN:

1089524

Other (OTH)

AF:

0.00

AC:

AN:

58532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

Peutz-Jeghers syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.063

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Benign

0.030

Eigen_PC

Benign

0.032

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.030

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.7

PhyloP100

3.2

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.49

REVEL

Benign

0.086

Sift

Benign

0.21

Sift4G

Benign

0.61

Polyphen

0.090

Vest4

0.51

MutPred

0.22

Gain of solvent accessibility (P = 0.0109)

MVP

0.27

MPC

0.063

ClinPred

0.42

GERP RS

3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.11

gMVP

0.46

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over