19-1226628-C-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_000455.5(STK11):​c.1283C>G​(p.Ser428Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000101 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S428L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:4
• 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: Benign. The variant received -8 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825
• BP6: Variant 19-1226628-C-G is Benign according to our data. Variant chr19-1226628-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 141156.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000101 (14/1390190) while in subpopulation AMR AF = 0.0002 (7/35042). AF 95% confidence interval is 0.0000937. There are 0 homozygotes in GnomAdExome4. There are 6 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 14 AD 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.1283C>G	p.Ser428Trp	missense	Exon 9 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NR_176325.1		n.2550C>G		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>G	p.Ser428Trp	missense	Exon 9 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000585748.3	TSL:3	c.911C>G	p.Ser304Trp	missense	Exon 11 of 12	ENSP00000477641.2	A0A087WT72
	STK11	ENST00000593219.6	TSL:3	n.*1108C>G		non_coding_transcript_exon	Exon 10 of 11	ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000355 AC: 5 AN: 140794 AF XY: 0.0000259

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000213

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: 0.0000101 AC: 14 AN: 1390190 Hom.: 0 Cov.: 31 AF XY: 0.00000875 AC XY: 6 AN XY: 685434

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

American (AMR) AF: 0.000200 AC: 7 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: 0.00000372 AC: 4 AN: 1076706

Other (OTH) AF: 0.0000521 AC: 3 AN: 57540

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000186 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	3	-	not provided (3)
-	2	-	not specified (2)
-	1	1	Peutz-Jeghers syndrome (2)
-	1	-	Peutz-Jeghers syndrome;C2931038:Familial pancreatic carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	-0.014	T
MutationAssessor	Benign	2.0	M
PhyloP100		4.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.35		Loss of phosphorylation at S428 (P = 0.0026)
MVP		0.64
MPC		0.32
ClinPred		0.65	D
GERP RS		3.0
Varity_R		0.45
gMVP		0.46
Mutation Taster		=37/63	disease causing

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: rs587781537; hg19: chr19-1226627;