dbSNP rs866664820: STK11:p.Ala295Asp (chr19-1221970-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_000455.5(STK11):c.884C>A(p.Ala295Asp) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A295S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.935

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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
familial ovarian cancer
Inheritance: AD 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 3 ACMG points.

PM1

In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 30 uncertain in NM_000455.5

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.36732316).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STK11	NM_000455.5	MANE Select	c.884C>A	p.Ala295Asp	missense	Exon 7 of 10	NP_000446.1
STK11	NM_001407255.1		c.884C>A	p.Ala295Asp	missense	Exon 7 of 9	NP_001394184.1
STK11	NR_176325.1		n.2151C>A		non_coding_transcript_exon	Exon 8 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STK11	ENST00000326873.12	TSL:1 MANE Select	c.884C>A	p.Ala295Asp	missense	Exon 7 of 10	ENSP00000324856.6
STK11	ENST00000652231.1		c.884C>A	p.Ala295Asp	missense	Exon 7 of 9	ENSP00000498804.1
STK11	ENST00000585748.3	TSL:3	c.512C>A	p.Ala171Asp	missense	Exon 9 of 12	ENSP00000477641.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1413506

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698880

African (AFR)

AF:

0.00

AC:

AN:

32122

American (AMR)

AF:

0.00

AC:

AN:

38022

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25366

East Asian (EAS)

AF:

0.00

AC:

AN:

36618

South Asian (SAS)

AF:

0.00

AC:

AN:

80218

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48802

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088080

Other (OTH)

AF:

0.00

AC:

AN:

58574

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.21

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.40

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.041

MetaRNN

Benign

0.37

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.33

PhyloP100

0.94

PrimateAI

Uncertain

0.51

PROVEAN

Benign

1.4

REVEL

Benign

0.19

Sift

Benign

0.65

Sift4G

Benign

0.74

Polyphen

0.0

Vest4

0.55

MutPred

0.36

Gain of ubiquitination at K296 (P = 0.0446)

MVP

0.35

MPC

0.055

ClinPred

0.40

GERP RS

3.6

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.0

Varity_R

0.22

gMVP

0.66

Mutation Taster

=52/48

polymorphism

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over