19-1222006-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The NM_000455.5(STK11):c.920G>T(p.Ser307Ile) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000705 in 1,417,480 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S307N) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: STK11 NM_000455.5 missense, splice_region
• Scores: Splicing: ADA: 0.9995
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.49

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STK11	NM_000455.5	c.920G>T	p.Ser307Ile	missense_variant, splice_region_variant	7/10	ENST00000326873.12
STK11	NM_001407255.1	c.920G>T	p.Ser307Ile	missense_variant, splice_region_variant	7/9
STK11	NR_176325.1	n.2187G>T		splice_region_variant, non_coding_transcript_exon_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STK11	ENST00000326873.12	c.920G>T	p.Ser307Ile	missense_variant, splice_region_variant	7/10	1	NM_000455.5	P1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1417480 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 701288

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000124

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
Cadd	Pathogenic	33
Dann	Uncertain	0.97
DEOGEN2	Benign	0.33	T;T
Eigen	Benign	-0.032
Eigen_PC	Benign	0.088
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Benign	0.044	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-0.46	T
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
Sift4G	Benign	0.23	T;T
Polyphen		0.048	.;B
Vest4		0.52
MutPred		0.58		Loss of disorder (P = 0.0152);Loss of disorder (P = 0.0152);
MVP		0.57
MPC		0.060
ClinPred		0.38	T
GERP RS		3.6
Varity_R		0.28
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1248289980; hg19: chr19-1222005;