dbSNP rs587782468: STK11:p.Ala205Glu (chr19-1220597-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.614C>A(p.Ala205Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. A205T) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

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: 7.80

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 domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 56 pathogenic changes around while only 19 benign (75%) 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.614C>A	p.Ala205Glu	missense_variant	Exon 5 of 10	ENST00000326873.12	NP_000446.1	Q15831-1A0A0S2Z4D1
STK11	NM_001407255.1 link	c.614C>A	p.Ala205Glu	missense_variant	Exon 5 of 9		NP_001394184.1
STK11	NR_176325.1 link	n.1881C>A		non_coding_transcript_exon_variant	Exon 6 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STK11	ENST00000326873.12 link	c.614C>A	p.Ala205Glu	missense_variant	Exon 5 of 10	1	NM_000455.5	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1 link	c.614C>A	p.Ala205Glu	missense_variant	Exon 5 of 9			ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3 link	c.242C>A	p.Ala81Glu	missense_variant	Exon 7 of 12	3		ENSP00000477641.2	A0A087WT72
STK11	ENST00000593219.6 link	n.*439C>A		non_coding_transcript_exon_variant	Exon 6 of 11	3		ENSP00000466610.1	K7EMR0
STK11	ENST00000593219.6 link	n.*439C>A		3_prime_UTR_variant	Exon 6 of 11	3		ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1437938

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713142

African (AFR)

AF:

0.00

AC:

AN:

32972

American (AMR)

AF:

0.00

AC:

AN:

41472

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25540

East Asian (EAS)

AF:

0.00

AC:

AN:

38546

South Asian (SAS)

AF:

0.00

AC:

AN:

83786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5658

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100516

Other (OTH)

AF:

0.00

AC:

AN:

59294

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.28

T;T;T

Eigen

Benign

0.046

Eigen_PC

Benign

0.077

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.22

MetaRNN

Uncertain

0.59

D;D;D

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-0.015

.;N;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-2.9

.;D;.

REVEL

Uncertain

0.34

Sift

Benign

0.035

.;D;.

Sift4G

Benign

0.49

T;T;T

Polyphen

0.86

.;P;.

Vest4

0.77

MutPred

0.36

Gain of solvent accessibility (P = 0.0261);Gain of solvent accessibility (P = 0.0261);.;

MVP

0.75

MPC

2.3

ClinPred

0.94

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.50

gMVP

0.94

Mutation Taster

=30/70

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.28

Position offset: 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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over