19-1220655-T-G

Variant names:

• chr19-1220655-T-G
• NM_000455.5:c.672T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000455.5(STK11):​c.672T>G​(p.Ile224Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.23

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 19 pathogenic changes around while only 5 benign (79%) in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.672T>G	p.Ile224Met	missense_variant	Exon 5 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.672T>G	p.Ile224Met	missense_variant	Exon 5 of 9		NP_001394184.1
STK11	NR_176325.1	n.1939T>G		non_coding_transcript_exon_variant	Exon 6 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.672T>G	p.Ile224Met	missense_variant	Exon 5 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.672T>G	p.Ile224Met	missense_variant	Exon 5 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.300T>G	p.Ile100Met	missense_variant	Exon 7 of 12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458358 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 725392

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T;T
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.89	D;D
MetaSVM	Uncertain	-0.15	T
MutationAssessor	Benign	0.72	.;N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.0	.;D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	.;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		1.0	.;D
Vest4		0.90
MutPred		0.76		Gain of disorder (P = 0.0384);Gain of disorder (P = 0.0384);
MVP		0.79
MPC		2.2
ClinPred		0.99	D
GERP RS		-11
Varity_R		0.89
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-1220654;