rs1555734959

Variant names:

• chr19-1207035-A-C
• rs1555734959
• NM_000455.5:c.122A>C

Your query was ambiguous. Multiple possible variants found:

• chr19-1207035-A-C
• chr19-1207035-A-G
• chr19-1207035-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_000455.5(STK11):​c.122A>C​(p.Lys41Thr) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K41N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.82
• Publications: 0 publications found

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

ACMG classification

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

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1207034-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4057254.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.794

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.122A>C	p.Lys41Thr	missense_variant	Exon 1 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.122A>C	p.Lys41Thr	missense_variant	Exon 1 of 9		NP_001394184.1
STK11	NR_176325.1	n.1258A>C		non_coding_transcript_exon_variant	Exon 1 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.122A>C	p.Lys41Thr	missense_variant	Exon 1 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.122A>C	p.Lys41Thr	missense_variant	Exon 1 of 9			ENSP00000498804.1
STK11	ENST00000593219.6	n.122A>C		non_coding_transcript_exon_variant	Exon 1 of 11	3		ENSP00000466610.1
STK11	ENST00000585748.3	c.-82-11382A>C		intron_variant	Intron 3 of 11	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Peutz-Jeghers syndrome Uncertain:1

May 09, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. This sequence change replaces lysine with threonine at codon 41 of the STK11 protein (p.Lys41Thr). The lysine residue is highly conserved and there is a moderate physicochemical difference between lysine and threonine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an STK11-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;D;T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Pathogenic	0.55	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.4	.;M;.
PhyloP100		8.8
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-4.1	.;D;.
REVEL	Pathogenic	0.76
Sift	Benign	0.035	.;D;.
Sift4G	Uncertain	0.045	D;D;T
Polyphen		0.95	.;P;.
Vest4		0.62
MutPred		0.40		Loss of methylation at K41 (P = 0.0151);Loss of methylation at K41 (P = 0.0151);Loss of methylation at K41 (P = 0.0151);
MVP		0.85
MPC		2.3
ClinPred		0.99	D
GERP RS		3.9
PromoterAI		-0.11	Neutral
Varity_R		0.43
gMVP		0.81
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs1555734959; hg19: chr19-1207034;