19-1220434-G-A

Variant names:

• chr19-1220434-G-A
• rs730881979
• NM_000455.5:c.526G>A

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PS3 PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000455.5(STK11):​c.526G>A​(p.Asp176Asn) 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 Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000629121: Experimental studies have shown that this missense change affects STK11 function (PMID:9837816, 10441497, 15987703)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D176A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 9.86
• Publications: 15 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 22 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000629121: Experimental studies have shown that this missense change affects STK11 function (PMID: 9837816, 10441497, 15987703).; SCV002642616: Functional studies of this alteration have also demonstrated severely reduced autophosphorylation compared to wild type STK11 in an in vitro protein kinase assay. This alteration also demonstrated subcellular localization similar to wildtype and maintained interaction with PTEN (Mehenni H et al. Am. J. Hum. Genet., 1998 Dec;63:1641-50; Mehenni H et al. Hum. Mol. Genet., 2005 Aug;14:2209-19).
• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 24 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1220434-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3963258.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 19-1220434-G-A is Pathogenic according to our data. Variant chr19-1220434-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 182907.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.526G>A	p.Asp176Asn	missense	Exon 4 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.526G>A	p.Asp176Asn	missense	Exon 4 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.1793G>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.526G>A	p.Asp176Asn	missense	Exon 4 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.526G>A	p.Asp176Asn	missense	Exon 4 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.154G>A	p.Asp52Asn	missense	Exon 6 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000423 AC: 1 AN: 236468 AF XY: 0.00000777

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 Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000108 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Peutz-Jeghers syndrome (2)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.36	T
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.71	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		9.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		1.0
MutPred		0.96		Loss of catalytic residue at D176 (P = 0.0452)
MVP		0.95
MPC		2.1
ClinPred		1.0	D
GERP RS		5.6
Varity_R		0.96
gMVP		0.97
Mutation Taster		=12/88	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: rs730881979; hg19: chr19-1220433; COSMIC: COSV58825680; COSMIC: COSV58825680;