rs1555738612

chr19-1221218-A-Cchr19-1221218-A-Gchr19-1221218-A-T

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.740A>C(p.Asn247Thr) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N247I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.98

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 hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.848

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.740A>C	p.Asn247Thr	missense_variant	6/10	ENST00000326873.12
STK11	NM_001407255.1	c.740A>C	p.Asn247Thr	missense_variant	6/9
STK11	NR_176325.1	n.2007A>C		non_coding_transcript_exon_variant	7/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.740A>C	p.Asn247Thr	missense_variant	6/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.32	T;D
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Uncertain	-0.21	T
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
Sift4G	Benign	0.099	T;T
Polyphen		1.0	.;D
Vest4		0.91
MutPred		0.50		Gain of glycosylation at T249 (P = 0.1923);Gain of glycosylation at T249 (P = 0.1923);
MVP		0.78
MPC		2.1
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.89
gMVP		0.91

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: chr19-1221217;