dbSNP rs549474196: STK11:p.Pro324Thr (chr19-1223034-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_000455.5(STK11):c.970C>A(p.Pro324Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000694 in 1,441,686 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. P324A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.80

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.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 37 uncertain in NM_000455.5

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.970C>A	p.Pro324Thr	missense_variant	Exon 8 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 link	c.970C>A	p.Pro324Thr	missense_variant	Exon 8 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.2237C>A		non_coding_transcript_exon_variant	Exon 9 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STK11	ENST00000326873.12 link	c.970C>A	p.Pro324Thr	missense_variant	Exon 8 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 link	c.970C>A	p.Pro324Thr	missense_variant	Exon 8 of 9			ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3 link	c.598C>A	p.Pro200Thr	missense_variant	Exon 10 of 12	3		ENSP00000477641.2	A0A087WT72
STK11	ENST00000593219.6 link	n.*795C>A		non_coding_transcript_exon_variant	Exon 9 of 11	3		ENSP00000466610.1	K7EMR0
STK11	ENST00000593219.6 link	n.*795C>A		3_prime_UTR_variant	Exon 9 of 11	3		ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.94e-7

AC:

AN:

1441686

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

715350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33076

American (AMR)

AF:

0.00

AC:

AN:

41916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25690

East Asian (EAS)

AF:

0.00

AC:

AN:

38666

South Asian (SAS)

AF:

0.00

AC:

AN:

83232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50670

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

9.07e-7

AC:

AN:

1103038

Other (OTH)

AF:

0.00

AC:

AN:

59656

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

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

0.016

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.35

T;D

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.20

FATHMM_MKL

Benign

0.68

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.62

D;D

MetaSVM

Uncertain

-0.018

MutationAssessor

Benign

2.0

.;M

PhyloP100

5.8

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.1

.;D

REVEL

Uncertain

0.34

Sift

Benign

0.048

.;D

Sift4G

Benign

0.14

T;T

Polyphen

0.28

.;B

Vest4

0.55

MutPred

0.40

Gain of phosphorylation at P324 (P = 0.0042);Gain of phosphorylation at P324 (P = 0.0042);

MVP

0.70

MPC

0.17

ClinPred

0.89

GERP RS

3.8

PromoterAI

-0.018

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.34

gMVP

0.46

Mutation Taster

=75/25

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

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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