Genetic Variant STK11:p.Lys41Arg (chr19-1207035-A-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PM5

The NM_000455.5(STK11):c.122A>G(p.Lys41Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,634 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K41N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 8.82

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 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-1207034-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4057254.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.122A>G	p.Lys41Arg	missense_variant	Exon 1 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 link	c.122A>G	p.Lys41Arg	missense_variant	Exon 1 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.1258A>G		non_coding_transcript_exon_variant	Exon 1 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STK11	ENST00000326873.12 link	c.122A>G	p.Lys41Arg	missense_variant	Exon 1 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 link	c.122A>G	p.Lys41Arg	missense_variant	Exon 1 of 9			ENSP00000498804.1	Q15831-2
STK11	ENST00000593219.6 link	n.122A>G		non_coding_transcript_exon_variant	Exon 1 of 11	3		ENSP00000466610.1	K7EMR0
STK11	ENST00000585748.3 link	c.-82-11382A>G		intron_variant	Intron 3 of 11	3		ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461634

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727096

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111862

Other (OTH)

AF:

0.00

AC:

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.099

BayesDel_noAF

Benign

-0.090

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;D;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Uncertain

0.15

MetaRNN

Uncertain

0.58

D;D;D

MetaSVM

Uncertain

0.30

MutationAssessor

Uncertain

2.4

.;M;.

PhyloP100

8.8

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.2

.;N;.

REVEL

Uncertain

0.55

Sift

Benign

0.042

.;D;.

Sift4G

Uncertain

0.017

D;D;D

Polyphen

0.87

.;P;.

Vest4

0.53

MutPred

0.32

Loss of methylation at K41 (P = 0.0175);Loss of methylation at K41 (P = 0.0175);Loss of methylation at K41 (P = 0.0175);

MVP

0.93

MPC

1.3

ClinPred

0.94

GERP RS

3.9

PromoterAI

-0.072

Neutral

(source)

Varity_R

0.24

gMVP

0.61

Mutation Taster

=49/51

disease causing

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over