rs754761142

Variant names:

• chr19-1221219-C-G
• rs754761142
• NM_000455.5:c.741C>G

Your query was ambiguous. Multiple possible variants found:

• chr19-1221219-C-G
• chr19-1221219-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000455.5(STK11):​c.741C>G​(p.Asn247Lys) 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 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. N247S) 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: 3.32
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 23 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.911

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	NM_000455.5	MANE Select	c.741C>G	p.Asn247Lys	missense	Exon 6 of 10	NP_000446.1
	STK11	NM_001407255.1		c.741C>G	p.Asn247Lys	missense	Exon 6 of 9	NP_001394184.1
	STK11	NR_176325.1		n.2008C>G		non_coding_transcript_exon	Exon 7 of 11

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.741C>G	p.Asn247Lys	missense	Exon 6 of 10	ENSP00000324856.6
	STK11	ENST00000652231.1		c.741C>G	p.Asn247Lys	missense	Exon 6 of 9	ENSP00000498804.1
	STK11	ENST00000585748.3	TSL:3	c.369C>G	p.Asn123Lys	missense	Exon 8 of 12	ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Benign	-0.21	N
PhyloP100		3.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.57
Sift	Uncertain	0.023	D
Sift4G	Benign	0.093	T
Polyphen		1.0	D
Vest4		0.95
MutPred		0.75		Gain of ubiquitination at N247 (P = 0.0247)
MVP		0.74
MPC		2.3
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.8
Varity_R		0.96
gMVP		0.96
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs754761142; hg19: chr19-1221218;