19-1221987-C-G

Position:

• chr19-1221987-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000455.5(STK11):​c.901C>G​(p.Arg301Gly) 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 benign outcome for this variant. 12/21 in silico tools predict a benign 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: 7.48

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 Uncertain_significance. Variant got 3 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.29687363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.901C>G	p.Arg301Gly	missense_variant	7/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.901C>G	p.Arg301Gly	missense_variant	7/9		NP_001394184.1
STK11	NR_176325.1	n.2168C>G		non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.901C>G	p.Arg301Gly	missense_variant	7/10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.901C>G	p.Arg301Gly	missense_variant	7/9			ENSP00000498804.1
STK11	ENST00000585748.3	c.529C>G	p.Arg177Gly	missense_variant	9/12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.00000557 AC: 1 AN: 179496 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 96768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000133

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000861 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.30	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.69	.;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-2.7	.;D
REVEL	Benign	0.11
Sift	Benign	0.059	.;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0020	.;B
Vest4		0.51
MutPred		0.42		Loss of MoRF binding (P = 0.0237);Loss of MoRF binding (P = 0.0237);
MVP		0.39
MPC		0.063
ClinPred		0.81	D
GERP RS		3.6
Varity_R		0.66
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs587780012; hg19: chr19-1221986;