Genetic Variant STK11:p.Asp194Glu (chr19-1220490-C-A) – ACMG Classification: Pathogenic (20 pts)

Variant summary

Our verdict is Pathogenic. The variant received 20 ACMG points: 20P and 0B. PS1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000455.5(STK11):c.582C>A(p.Asp194Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D194H) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

STK11
NM_000455.5 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 3.22

Publications

6 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:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 20 ACMG points.

PS1

Transcript NM_000455.5 (STK11) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-1220488-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1027310.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 19-1220490-C-A is Pathogenic according to our data. Variant chr19-1220490-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 185384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STK11	NM_000455.5	MANE Select	c.582C>A	p.Asp194Glu	missense	Exon 4 of 10	NP_000446.1
STK11	NM_001407255.1		c.582C>A	p.Asp194Glu	missense	Exon 4 of 9	NP_001394184.1
STK11	NR_176325.1		n.1849C>A		non_coding_transcript_exon	Exon 5 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
STK11	ENST00000326873.12	TSL:1 MANE Select	c.582C>A	p.Asp194Glu	missense	Exon 4 of 10	ENSP00000324856.6
STK11	ENST00000652231.1		c.582C>A	p.Asp194Glu	missense	Exon 4 of 9	ENSP00000498804.1
STK11	ENST00000585748.3	TSL:3	c.210C>A	p.Asp70Glu	missense	Exon 6 of 12	ENSP00000477641.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary cancer-predisposing syndrome (1)

not provided (1)

Peutz-Jeghers syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

Eigen

Pathogenic

0.78

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.65

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

PhyloP100

3.2

PrimateAI

Pathogenic

0.91

PROVEAN

Uncertain

-4.0

REVEL

Pathogenic

0.84

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.99

MutPred

0.97

Loss of ubiquitination at K191 (P = 0.1473)

MVP

1.0

MPC

2.1

ClinPred

1.0

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.95

gMVP

0.99

Mutation Taster

=3/97

disease causing (ClinVar)

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over