19-1218443-G-T

Variant names:

• chr19-1218443-G-T
• rs375622587
• ENST00000585748.3:c.-56G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000585748.3(STK11):​c.-56G>T variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.00000274 in 1,461,324 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: STK11 ENST00000585748.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.50
• 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, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• familial ovarian cancer

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000585748.3. 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.317G>T	p.Arg106Leu	missense	Exon 2 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.317G>T	p.Arg106Leu	missense	Exon 2 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.1584G>T		non_coding_transcript_exon	Exon 3 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000585748.3	TSL:3	c.-56G>T		5_prime_UTR_premature_start_codon_gain	Exon 4 of 12	ENSP00000477641.2	A0A087WT72
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.317G>T	p.Arg106Leu	missense	Exon 2 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.317G>T	p.Arg106Leu	missense	Exon 2 of 9	ENSP00000498804.1	Q15831-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461324 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 726928

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53128

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111786

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Hereditary cancer-predisposing syndrome (2)
-	2	-	Peutz-Jeghers syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.050	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.16	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.014	D
MutationAssessor	Benign	1.9	L
PhyloP100		4.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.39
Sift	Uncertain	0.023	D
Sift4G	Benign	0.14	T
Polyphen		0.80	P
Vest4		0.56
MutPred		0.49		Loss of MoRF binding (P = 0.0528)
MVP		0.63
MPC		1.4
ClinPred		0.97	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.49
Mutation Taster		=68/32	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: rs375622587; hg19: chr19-1218442;