19-1223034-C-T

Variant names:

• chr19-1223034-C-T
• rs549474196
• NM_000455.5:c.970C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000455.5(STK11):​c.970C>T​(p.Pro324Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000314 in 1,593,832 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P324A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:9
• Conservation: PhyloP100: 5.80
• Publications: 5 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 37 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage

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.970C>T	p.Pro324Ser	missense	Exon 8 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.970C>T	p.Pro324Ser	missense	Exon 8 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.2237C>T		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.970C>T	p.Pro324Ser	missense	Exon 8 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.970C>T	p.Pro324Ser	missense	Exon 8 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.598C>T	p.Pro200Ser	missense	Exon 10 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

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

GnomAD4 exome AF: 0.00000208 AC: 3 AN: 1441686 Hom.: 0 Cov.: 31 AF XY: 0.00000280 AC XY: 2 AN XY: 715350

African (AFR) AF: 0.00 AC: 0 AN: 33076

American (AMR) AF: 0.00 AC: 0 AN: 41916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25690

East Asian (EAS) AF: 0.00 AC: 0 AN: 38666

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50670

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1103038

Other (OTH) AF: 0.00 AC: 0 AN: 59656

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152146 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74320

African (AFR) AF: 0.00 AC: 0 AN: 41412

American (AMR) AF: 0.0000654 AC: 1 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	5	-	Peutz-Jeghers syndrome (5)
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.018	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.43	T
MetaSVM	Uncertain	-0.10	T
MutationAssessor	Benign	2.0	M
PhyloP100		5.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.31
Sift	Benign	0.10	T
Sift4G	Benign	0.067	T
Polyphen		0.14	B
Vest4		0.50
MutPred		0.29		Loss of helix (P = 0.0068)
MVP		0.71
MPC		0.16
ClinPred		0.83	D
GERP RS		3.8
PromoterAI		-0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.42
Mutation Taster		=74/26	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: rs549474196; hg19: chr19-1223033; COSMIC: COSV105889066;