rs1555738276

Variant names:

• chr19-1220491-C-A
• rs1555738276
• NM_000455.5:c.583C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1220491-C-A
• chr19-1220491-C-G
• chr19-1220491-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000455.5(STK11):​c.583C>A​(p.Leu195Met) 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. L195R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.24
• 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.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 34 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.819

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.583C>A	p.Leu195Met	missense	Exon 4 of 10	NP_000446.1
	STK11	NM_001407255.1		c.583C>A	p.Leu195Met	missense	Exon 4 of 9	NP_001394184.1
	STK11	NR_176325.1		n.1850C>A		non_coding_transcript_exon	Exon 5 of 11

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.583C>A	p.Leu195Met	missense	Exon 4 of 10	ENSP00000324856.6
	STK11	ENST00000652231.1		c.583C>A	p.Leu195Met	missense	Exon 4 of 9	ENSP00000498804.1
	STK11	ENST00000585748.3	TSL:3	c.211C>A	p.Leu71Met	missense	Exon 6 of 12	ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 6.88e-7 AC: 1 AN: 1452554 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 721766

African (AFR) AF: 0.00 AC: 0 AN: 33348

American (AMR) AF: 0.00 AC: 0 AN: 43698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39330

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51454

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108212

Other (OTH) AF: 0.00 AC: 0 AN: 60026

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	-0.0065	T
MutationAssessor	Benign	1.1	L
PhyloP100		3.2
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.68		Gain of ubiquitination at K191 (P = 0.1025)
MVP		0.76
MPC		2.1
ClinPred		0.88	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.83
Mutation Taster		=78/22	polymorphism

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: rs1555738276; hg19: chr19-1220490; COSMIC: COSV58827832; COSMIC: COSV58827832;