dbSNP rs786201244: STK11:p.Ser422Arg (chr19-1226611-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.1266C>A(p.Ser422Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,404,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S422P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.11

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21271753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5 link	c.1266C>A	p.Ser422Arg	missense_variant	Exon 9 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NR_176325.1 link	n.2533C>A		non_coding_transcript_exon_variant	Exon 10 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STK11	ENST00000326873.12 link	c.1266C>A	p.Ser422Arg	missense_variant	Exon 9 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000585748.3 link	c.894C>A	p.Ser298Arg	missense_variant	Exon 11 of 12	3		ENSP00000477641.2	A0A087WT72
STK11	ENST00000593219.6 link	n.*1091C>A		non_coding_transcript_exon_variant	Exon 10 of 11	3		ENSP00000466610.1	K7EMR0
STK11	ENST00000593219.6 link	n.*1091C>A		3_prime_UTR_variant	Exon 10 of 11	3		ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.12e-7

AC:

AN:

1404256

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

693598

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31582

American (AMR)

AF:

0.00

AC:

AN:

36572

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25110

East Asian (EAS)

AF:

0.00

AC:

AN:

36218

South Asian (SAS)

AF:

0.00

AC:

AN:

79834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47718

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4980

European-Non Finnish (NFE)

AF:

9.22e-7

AC:

AN:

1084134

Other (OTH)

AF:

0.00

AC:

AN:

58108

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

Pathogenic

0.58

BayesDel_addAF

Benign

0.0012

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

T;T

Eigen

Benign

-0.15

Eigen_PC

Benign

-0.035

FATHMM_MKL

Uncertain

0.83

LIST_S2

Benign

0.79

T;T

M_CAP

Benign

0.066

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

1.9

.;L

PhyloP100

3.1

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.74

.;N

REVEL

Benign

0.21

Sift

Benign

0.13

.;T

Sift4G

Benign

0.39

T;T

Polyphen

0.0010

.;B

Vest4

0.31

MutPred

0.21

.;Loss of phosphorylation at S422 (P = 0.0101);

MVP

0.65

MPC

0.045

ClinPred

0.68

GERP RS

3.2

Varity_R

0.25

gMVP

0.52

Mutation Taster

=44/56

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