rs1060499958

Positions:

• chr19-1219356-T-A
• chr19-1219356-T-C
• chr19-1219356-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000455.5(STK11):​c.407T>A​(p.Met136Lys) variant causes a missense 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 34)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.78

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.407T>A	p.Met136Lys	missense_variant	3/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.407T>A	p.Met136Lys	missense_variant	3/9		NP_001394184.1
STK11	NR_176325.1	n.1674T>A		non_coding_transcript_exon_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.407T>A	p.Met136Lys	missense_variant	3/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.407T>A	p.Met136Lys	missense_variant	3/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.35T>A	p.Met12Lys	missense_variant	5/12	3		ENSP00000477641.2
STK11	ENST00000593219.5	n.*232T>A		splice_region_variant, non_coding_transcript_exon_variant	4/4	3		ENSP00000466610.1
STK11	ENST00000593219.5	n.*232T>A		3_prime_UTR_variant	4/4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	.;T;D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.80	T;D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.086	D
MutationAssessor	Benign	0.69	.;.;N
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-4.3	.;.;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	.;.;D
Sift4G	Uncertain	0.0020	.;D;D
Polyphen		0.98	.;.;D
Vest4		0.96, 0.86
MutPred		0.76		.;Gain of methylation at M136 (P = 0.0047);Gain of methylation at M136 (P = 0.0047);
MVP		0.90
MPC		2.5
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.8
Varity_R		0.95
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-1219355; COSMIC: COSV100480034; COSMIC: COSV100480034;