rs587781537

Variant names:

• chr19-1226628-C-A
• rs587781537
• NM_000455.5:c.1283C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1226628-C-A
• chr19-1226628-C-G
• chr19-1226628-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_000455.5(STK11):​c.1283C>A​(p.Ser428*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000719 in 1,390,190 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S428S) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: STK11 NM_000455.5 stop_gained
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.68
• Publications: 10 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: ClinGen, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Orphanet
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0146 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	NM_000455.5	MANE Select	c.1283C>A	p.Ser428*	stop_gained	Exon 9 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NR_176325.1		n.2550C>A		non_coding_transcript_exon	Exon 10 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.1283C>A	p.Ser428*	stop_gained	Exon 9 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000585748.3	TSL:3	c.911C>A	p.Ser304*	stop_gained	Exon 11 of 12	ENSP00000477641.2	A0A087WT72
	STK11	ENST00000593219.6	TSL:3	n.*1108C>A		non_coding_transcript_exon	Exon 10 of 11	ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000710 AC: 1 AN: 140794 AF XY: 0.0000130

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000188

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1390190 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 685434

African (AFR) AF: 0.00 AC: 0 AN: 31118

American (AMR) AF: 0.00 AC: 0 AN: 35042

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24876

East Asian (EAS) AF: 0.00 AC: 0 AN: 35630

South Asian (SAS) AF: 0.00 AC: 0 AN: 79010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45664

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4604

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076706

Other (OTH) AF: 0.00 AC: 0 AN: 57540

GnomAD4 genome Cov.: 33

Alfa AF: 0.000761 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Peutz-Jeghers syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	44
DANN	Uncertain	1.0
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		4.7
Vest4		0.81
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=23/177	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: rs587781537; hg19: chr19-1226627;