rs398123405

Variant names:

• chr19-1221963-G-A
• rs398123405
• NM_000455.5:c.877G>A
• STK11 p.Glu293Lys

Your query was ambiguous. Multiple possible variants found:

• chr19-1221963-G-A
• chr19-1221963-G-C
• chr19-1221963-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM1 BP6 BS2

The NM_000455.5(STK11):​c.877G>A​(p.Glu293Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,410,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E293Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:2
• Conservation: PhyloP100: 7.27
• Publications: 3 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: Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, ClinGen
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 32 uncertain in NM_000455.5
• BP6: Variant 19-1221963-G-A is Benign according to our data. Variant chr19-1221963-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142641.
• BS2: High AC in GnomAdExome4 at 6 AD,Unknown gene.

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.877G>A	p.Glu293Lys	missense	Exon 7 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.877G>A	p.Glu293Lys	missense	Exon 7 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.2144G>A		non_coding_transcript_exon	Exon 8 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.877G>A	p.Glu293Lys	missense	Exon 7 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.877G>A	p.Glu293Lys	missense	Exon 7 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.505G>A	p.Glu169Lys	missense	Exon 9 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.0000116 AC: 2 AN: 172130 AF XY: 0.0000217

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000425 AC: 6 AN: 1410818 Hom.: 0 Cov.: 30 AF XY: 0.00000717 AC XY: 5 AN XY: 697290

African (AFR) AF: 0.00 AC: 0 AN: 32022

American (AMR) AF: 0.00 AC: 0 AN: 37620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25340

East Asian (EAS) AF: 0.00 AC: 0 AN: 36450

South Asian (SAS) AF: 0.0000250 AC: 2 AN: 80000

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5702

European-Non Finnish (NFE) AF: 0.00000368 AC: 4 AN: 1086606

Other (OTH) AF: 0.00 AC: 0 AN: 58464

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	-	Peutz-Jeghers syndrome (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.075
Eigen_PC	Benign	0.0090
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.0	L
PhyloP100		7.3
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-2.4	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.012	D
Varity_R		0.49
gMVP		0.59
Mutation Taster		=64/36	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs398123405;

hg19: chr19-1221962;