19-1220595-C-G

Variant names:

• chr19-1220595-C-G
• rs774100153
• NM_000455.5:c.612C>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000455.5(STK11):​c.612C>G​(p.Phe204Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,436,044 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 Uncertain significance (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F204V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (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:4
• Conservation: PhyloP100: 0.243
• Publications: 1 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.745

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.612C>G	p.Phe204Leu	missense	Exon 5 of 10	NP_000446.1	A0A0S2Z4D1
	STK11	NM_001407255.1		c.612C>G	p.Phe204Leu	missense	Exon 5 of 9	NP_001394184.1	Q15831-2
	STK11	NR_176325.1		n.1879C>G		non_coding_transcript_exon	Exon 6 of 11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.612C>G	p.Phe204Leu	missense	Exon 5 of 10	ENSP00000324856.6	Q15831-1
	STK11	ENST00000652231.1		c.612C>G	p.Phe204Leu	missense	Exon 5 of 9	ENSP00000498804.1	Q15831-2
	STK11	ENST00000585748.3	TSL:3	c.240C>G	p.Phe80Leu	missense	Exon 7 of 12	ENSP00000477641.2	A0A087WT72

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000966 AC: 2 AN: 207118 AF XY: 0.00

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: 0.0000221

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1436044 Hom.: 0 Cov.: 32 AF XY: 0.00000281 AC XY: 2 AN XY: 711944

African (AFR) AF: 0.00 AC: 0 AN: 32902

American (AMR) AF: 0.00 AC: 0 AN: 41364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25524

East Asian (EAS) AF: 0.00 AC: 0 AN: 38422

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50038

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5668

European-Non Finnish (NFE) AF: 0.00000182 AC: 2 AN: 1099352

Other (OTH) AF: 0.00 AC: 0 AN: 59196

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000410 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000844 AC: 1

ClinVar

ClinVar submissions

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	Pathogenic	0.97
BayesDel_addAF	Benign	-0.0095	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	14
DANN	Uncertain	0.97
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.70	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.83	L
PhyloP100		0.24
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.037	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.45		Gain of relative solvent accessibility (P = 0.0479)
MVP		0.55
MPC		2.3
ClinPred		0.97	D
GERP RS		-5.3
Varity_R		0.79
gMVP		0.82
Mutation Taster		=4/96	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs774100153; hg19: chr19-1220594;