rs121913315

Variant names:

• chr19-1220488-G-A
• rs121913315
• NM_000455.5:c.580G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1220488-G-A
• chr19-1220488-G-C
• chr19-1220488-G-T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000455.5(STK11):​c.580G>A​(p.Asp194Asn) 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. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D194H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12
• Conservation: PhyloP100: 9.86
• Publications: 83 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: Pathogenic. The variant received 16 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1220488-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1027310.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.991
• PP5: Variant 19-1220488-G-A is Pathogenic according to our data. Variant chr19-1220488-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 188348.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.580G>A	p.Asp194Asn	missense	Exon 4 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.580G>A	p.Asp194Asn	missense	Exon 4 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.1847G>A		non_coding_transcript_exon	Exon 5 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.580G>A	p.Asp194Asn	missense	Exon 4 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.580G>A	p.Asp194Asn	missense	Exon 4 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.208G>A	p.Asp70Asn	missense	Exon 6 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1453076 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 722074

African (AFR) AF: 0.00 AC: 0 AN: 33366

American (AMR) AF: 0.00 AC: 0 AN: 43768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25906

East Asian (EAS) AF: 0.00 AC: 0 AN: 39338

South Asian (SAS) AF: 0.00 AC: 0 AN: 84898

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108506

Other (OTH) AF: 0.00 AC: 0 AN: 60034

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000432 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	not provided (7)
3	-	-	Peutz-Jeghers syndrome (3)
2	-	-	Hereditary cancer-predisposing syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.98		Gain of sheet (P = 0.0827)
MVP		0.96
MPC		2.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.99
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs121913315; hg19: chr19-1220487; COSMIC: COSV58820976; COSMIC: COSV58820976;