Genetic Variant NM_000455.5:c.463G>C (chr19-1219412-G-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1PM2PP3

The NM_000455.5(STK11):c.463G>C(p.Gly155Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). 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. G155E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 34)

Consequence

STK11
NM_000455.5 missense, splice_region

Scores

Splicing: ADA: 0.002764

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.70

Publications

4 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet
familial ovarian cancer
Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

STK11 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 36 uncertain in NM_000455.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.755

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	UniProt
STK11	NM_000455.5	MANE Select	c.463G>C	p.Gly155Arg	missense splice_region	Exon 3 of 10	NP_000446.1	A0A0S2Z4D1
STK11	NM_001407255.1		c.463G>C	p.Gly155Arg	missense splice_region	Exon 3 of 9	NP_001394184.1	Q15831-2
STK11	NR_176325.1		n.1730G>C		splice_region non_coding_transcript_exon	Exon 4 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STK11	ENST00000326873.12	TSL:1 MANE Select	c.463G>C	p.Gly155Arg	missense splice_region	Exon 3 of 10	ENSP00000324856.6	Q15831-1
STK11	ENST00000652231.1		c.463G>C	p.Gly155Arg	missense splice_region	Exon 3 of 9	ENSP00000498804.1	Q15831-2
STK11	ENST00000585748.3	TSL:3	c.91G>C	p.Gly31Arg	missense splice_region	Exon 5 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Melanoma, cutaneous malignant, susceptibility to, 1 (1)

Peutz-Jeghers syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.31

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.0052

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.076

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.17

PhyloP100

9.7

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.38

Sift

Benign

0.45

Sift4G

Benign

0.58

Polyphen

0.64

Vest4

0.94

MutPred

0.53

Loss of catalytic residue at C158 (P = 0.0867)

MVP

0.66

MPC

1.2

ClinPred

0.91

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.93

Mutation Taster

=12/88

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0028

dbscSNV1_RF

Benign

0.066

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