19-1226474-G-C

Variant names:

• chr19-1226474-G-C
• rs768870802
• NM_000455.5:c.1129G>C

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.1129G>C​(p.Ala377Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,458,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. A377G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 1.46
• Publications: 2 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=0.105909646).
• BP6: Variant 19-1226474-G-C is Benign according to our data. Variant chr19-1226474-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 237789.
• 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.1129G>C	p.Ala377Pro	missense	Exon 9 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NR_176325.1		n.2396G>C		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.1129G>C	p.Ala377Pro	missense	Exon 9 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000585748.3	TSL:3	c.757G>C	p.Ala253Pro	missense	Exon 11 of 12	ENSP00000477641.2	A0A087WT72
	STK11	ENST00000593219.6	TSL:3	n.*954G>C		non_coding_transcript_exon	Exon 10 of 11	ENSP00000466610.1	K7EMR0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000827 AC: 2 AN: 241710 AF XY: 0.0000151

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: 0.0000185

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458964 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 725688

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.00 AC: 0 AN: 44594

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26052

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111308

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Hereditary cancer-predisposing syndrome (3)
-	2	1	Peutz-Jeghers syndrome (3)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.5	L
PhyloP100		1.5
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.041
Sift	Benign	0.27	T
Sift4G	Benign	0.31	T
Polyphen		0.17	B
Vest4		0.21
MutPred		0.34		Loss of sheet (P = 0.0142)
MVP		0.61
MPC		0.062
ClinPred		0.14	T
GERP RS		2.2
Varity_R		0.26
gMVP		0.42
Mutation Taster		=67/33	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: rs768870802; hg19: chr19-1226473;