chr19-1223076-G-A

Variant names:

• chr19-1223076-G-A
• rs587782302
• NM_000455.5:c.1012G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_000455.5(STK11):​c.1012G>A​(p.Val338Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000286 in 1,608,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. V338A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:11 B:3
• Conservation: PhyloP100: 5.52
• 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: 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18768993).
• BP6: Variant 19-1223076-G-A is Benign according to our data. Variant chr19-1223076-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 142198.
• BS2: High AC in GnomAdExome4 at 44 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.1012G>A	p.Val338Met	missense	Exon 8 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.1012G>A	p.Val338Met	missense	Exon 8 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.2279G>A		non_coding_transcript_exon	Exon 9 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.1012G>A	p.Val338Met	missense	Exon 8 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.1012G>A	p.Val338Met	missense	Exon 8 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.640G>A	p.Val214Met	missense	Exon 10 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151862 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000209 AC: 5 AN: 238888 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000204

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000278

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000302 AC: 44 AN: 1456530 Hom.: 0 Cov.: 31 AF XY: 0.0000304 AC XY: 22 AN XY: 724052

African (AFR) AF: 0.00 AC: 0 AN: 33408

American (AMR) AF: 0.00 AC: 0 AN: 44274

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26022

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.00 AC: 0 AN: 85282

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51834

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.0000333 AC: 37 AN: 1110200

Other (OTH) AF: 0.0000332 AC: 2 AN: 60216

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151862 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 74130

African (AFR) AF: 0.00 AC: 0 AN: 41322

American (AMR) AF: 0.00 AC: 0 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2084

Alfa AF: 0.0000450 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000249 AC: 3

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	4	1	Peutz-Jeghers syndrome (5)
-	2	1	Hereditary cancer-predisposing syndrome (3)
-	1	1	not provided (2)
-	1	-	Familial adenomatous polyposis 2 (1)
-	1	-	Generalized juvenile polyposis/juvenile polyposis coli (1)
-	1	-	Peutz-Jeghers syndrome;C0153594:Malignant tumor of testis;C0235974:Carcinoma of pancreas (1)
-	1	-	STK11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.53	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.074	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	2.0	M
PhyloP100		5.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.28	N
REVEL	Benign	0.13
Sift	Benign	0.076	T
Sift4G	Benign	0.11	T
Polyphen		0.0030	B
Vest4		0.43
MutPred		0.34		Gain of disorder (P = 0.0484)
MVP		0.41
MPC		0.042
ClinPred		0.23	T
GERP RS		2.8
PromoterAI		0.038	Neutral
Varity_R		0.16
gMVP		0.48
Mutation Taster		=70/30	polymorphism

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: rs587782302; hg19: chr19-1223075; COSMIC: COSV105889174;