19-1221997-G-T

Variant names:

• chr19-1221997-G-T
• NM_000455.5:c.911G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000455.5(STK11):​c.911G>T​(p.Arg304Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000705 in 1,418,520 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R304W) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.57

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 7 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-1221996-C-T is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.813

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.911G>T	p.Arg304Leu	missense_variant	Exon 7 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.911G>T	p.Arg304Leu	missense_variant	Exon 7 of 9		NP_001394184.1
STK11	NR_176325.1	n.2178G>T		non_coding_transcript_exon_variant	Exon 8 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.911G>T	p.Arg304Leu	missense_variant	Exon 7 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.911G>T	p.Arg304Leu	missense_variant	Exon 7 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.539G>T	p.Arg180Leu	missense_variant	Exon 9 of 12	3		ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.05e-7 AC: 1 AN: 1418520 Hom.: 0 Cov.: 30 AF XY: 0.00000142 AC XY: 1 AN XY: 701900

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: 9.17e-7

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	Uncertain	0.54
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;D
Eigen	Benign	0.016
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-1.7	.;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Pathogenic	-4.6	.;D
REVEL	Uncertain	0.53
Sift	Uncertain	0.0040	.;D
Sift4G	Benign	0.18	T;T
Polyphen		0.86	.;P
Vest4		0.76
MutPred		0.68		Loss of disorder (P = 0.0347);Loss of disorder (P = 0.0347);
MVP		0.82
MPC		0.30
ClinPred		0.99	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.82

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-1221996;