19-1223040-C-T

Position:

• chr19-1223040-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000455.5(STK11):​c.976C>T​(p.Pro326Ser) 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 benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11175412).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
STK11	NM_000455.5	c.976C>T	p.Pro326Ser	missense_variant	8/10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.976C>T	p.Pro326Ser	missense_variant	8/9		NP_001394184.1
STK11	NR_176325.1	n.2243C>T		non_coding_transcript_exon_variant	9/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.976C>T	p.Pro326Ser	missense_variant	8/10	1	NM_000455.5	ENSP00000324856	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 12, 2021

This sequence change replaces proline with serine at codon 326 of the STK11 protein (p.Pro326Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt STK11 protein function. This variant has not been reported in the literature in individuals affected with STK11-related conditions. This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.90
DEOGEN2	Benign	0.25	T;T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.11	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.5	.;L
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.080	.;N
REVEL	Benign	0.12
Sift	Benign	0.36	.;T
Sift4G	Benign	0.74	T;T
Polyphen		0.0070	.;B
Vest4		0.20
MutPred		0.29		Gain of phosphorylation at P326 (P = 0.0298);Gain of phosphorylation at P326 (P = 0.0298);
MVP		0.56
MPC		0.042
ClinPred		0.15	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.022
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr19-1223039;