dbSNP rs587780715: STK11:p.Cys418* (chr19-1226599-C-A) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_000455.5(STK11):c.1254C>A(p.Cys418*) variant causes a stop gained change involving the alteration of a non-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. Synonymous variant affecting the same amino acid position (i.e. C418C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

STK11
NM_000455.5 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.505

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: Pathogenic. The variant received 10 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

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.1254C>A	p.Cys418*	stop_gained	Exon 9 of 10	ENST00000326873.12	NP_000446.1
STK11	NR_176325.1 link	n.2521C>A		non_coding_transcript_exon_variant	Exon 10 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
STK11	ENST00000326873.12 link	c.1254C>A	p.Cys418*	stop_gained	Exon 9 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000585748.3 link	c.882C>A	p.Cys294*	stop_gained	Exon 11 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6 link	n.*1079C>A		non_coding_transcript_exon_variant	Exon 10 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6 link	n.*1079C>A		3_prime_UTR_variant	Exon 10 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1412506

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

698510

African (AFR)

AF:

0.00

AC:

AN:

31898

American (AMR)

AF:

0.00

AC:

AN:

37556

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25270

East Asian (EAS)

AF:

0.00

AC:

AN:

36602

South Asian (SAS)

AF:

0.00

AC:

AN:

80444

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48382

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5224

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088656

Other (OTH)

AF:

0.00

AC:

AN:

58474

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.45

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Uncertain

0.37

Eigen_PC

Benign

0.076

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.32

MetaRNN

Uncertain

0.55

MetaSVM

Benign

-1.0

PhyloP100

0.51

Sift4G

Benign

0.61

Vest4

0.48

MVP

0.85

ClinPred

0.95

GERP RS

0.87

Mutation Taster

=38/162

disease causing (fs/PTC)

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over