NM_000455.5:c.434A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1BP4BS2

The NM_000455.5(STK11):c.434A>G(p.Glu145Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000113 in 1,506,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. E145K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11B:1

Conservation

PhyloP100: 7.30

Publications

2 publications found

Variant links:

COSMIC-nc: COSV105889167

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: Likely_benign. The variant received -3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 38 uncertain in NM_000455.5

BP4

Computational evidence support a benign effect (MetaRNN=0.34022498).

BS2

High AC in GnomAdExome4 at 15 AD,Unknown gene.

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	UniProt
STK11	NM_000455.5	MANE Select	c.434A>G	p.Glu145Gly	missense	Exon 3 of 10	NP_000446.1	A0A0S2Z4D1
STK11	NM_001407255.1		c.434A>G	p.Glu145Gly	missense	Exon 3 of 9	NP_001394184.1	Q15831-2
STK11	NR_176325.1		n.1701A>G		non_coding_transcript_exon	Exon 4 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STK11	ENST00000326873.12	TSL:1 MANE Select	c.434A>G	p.Glu145Gly	missense	Exon 3 of 10	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1		c.434A>G	p.Glu145Gly	missense	Exon 3 of 9	ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3	TSL:3	c.62A>G	p.Glu21Gly	missense	Exon 5 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes

AF:

0.0000135

AC:

AN:

148478

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000298

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000134

AC:

AN:

224084

AF XY:

0.00000824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000198

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000110

AC:

AN:

1358066

Hom.:

Cov.:

AF XY:

0.00000594

AC XY:

AN XY:

673660

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30588

American (AMR)

AF:

0.00

AC:

AN:

40060

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22398

East Asian (EAS)

AF:

0.00

AC:

AN:

23808

South Asian (SAS)

AF:

0.00

AC:

AN:

82386

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43948

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5154

European-Non Finnish (NFE)

AF:

0.0000142

AC:

AN:

1055906

Other (OTH)

AF:

0.00

AC:

AN:

53818

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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

AF:

0.0000135

AC:

AN:

148478

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

72462

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

40798

American (AMR)

AF:

0.00

AC:

AN:

14956

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3428

East Asian (EAS)

AF:

0.00

AC:

AN:

4380

South Asian (SAS)

AF:

0.00

AC:

AN:

4444

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10068

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.0000298

AC:

AN:

67124

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000117

AC:

ExAC

AF:

0.00000833

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Peutz-Jeghers syndrome (6)

Hereditary cancer-predisposing syndrome (2)

not provided (2)

not specified (1)

Peutz-Jeghers syndrome;C1336708:Germ cell tumor of testis;C1835047:Melanoma, cutaneous malignant, susceptibility to, 1;C2931038:Familial pancreatic carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

0.0033

BayesDel_noAF

Benign

-0.23

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.14

Eigen_PC

Benign

0.019

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.81

M_CAP

Benign

0.048

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

PhyloP100

7.3

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.6

REVEL

Benign

0.23

Sift

Benign

0.33

Sift4G

Benign

0.34

Polyphen

0.0010

Vest4

0.52

MVP

0.55

MPC

1.1

ClinPred

0.66

GERP RS

4.9

Varity_R

0.36

gMVP

0.70

Mutation Taster

=67/33

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over