19-1207070-G-C

Variant names:

• chr19-1207070-G-C
• NM_000455.5:c.157G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3_Moderate

The NM_000455.5(STK11):​c.157G>C​(p.Asp53His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. D53?) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.65

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 8 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 chr19-1207069-GGA-GT is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.157G>C	p.Asp53His	missense_variant	Exon 1 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.157G>C	p.Asp53His	missense_variant	Exon 1 of 9		NP_001394184.1
STK11	NR_176325.1	n.1293G>C		non_coding_transcript_exon_variant	Exon 1 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.157G>C	p.Asp53His	missense_variant	Exon 1 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.157G>C	p.Asp53His	missense_variant	Exon 1 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.-82-11347G>C		intron_variant	Intron 3 of 11	3		ENSP00000477641.2
STK11	ENST00000593219.5	n.157G>C		non_coding_transcript_exon_variant	Exon 1 of 4	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;D;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.55	D
MutationAssessor	Benign	1.5	.;L;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.4	.;D;.
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0020	.;D;.
Sift4G	Uncertain	0.0050	D;D;D
Polyphen		1.0	.;D;.
Vest4		0.80
MutPred		0.48		Gain of MoRF binding (P = 0.0546);Gain of MoRF binding (P = 0.0546);Gain of MoRF binding (P = 0.0546);
MVP		0.81
MPC		2.3
ClinPred		1.0	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.65

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: chr19-1207069;