19-1207038-G-C

Variant names:

• chr19-1207038-G-C
• rs148830698
• NM_000455.5:c.125G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000455.5(STK11):​c.125G>C​(p.Arg42Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. R42L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.62
• Publications: 0 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Genomics England PanelApp, G2P
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 43 uncertain in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.125G>C	p.Arg42Pro	missense_variant	Exon 1 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.125G>C	p.Arg42Pro	missense_variant	Exon 1 of 9		NP_001394184.1
STK11	NR_176325.1	n.1261G>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.125G>C	p.Arg42Pro	missense_variant	Exon 1 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.125G>C	p.Arg42Pro	missense_variant	Exon 1 of 9			ENSP00000498804.1
STK11	ENST00000593219.6	n.125G>C		non_coding_transcript_exon_variant	Exon 1 of 11	3		ENSP00000466610.1
STK11	ENST00000585748.3	c.-82-11379G>C		intron_variant	Intron 3 of 11	3		ENSP00000477641.2

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	0.93
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Pathogenic	27
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;D;T
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.10
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.69	D;D;D
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.4	.;L;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.2	.;D;.
REVEL	Uncertain	0.47
Sift	Benign	0.24	.;T;.
Sift4G	Benign	0.10	T;T;T
Polyphen		0.0020	.;B;.
Vest4		0.72
MutPred		0.57		Loss of MoRF binding (P = 0.012);Loss of MoRF binding (P = 0.012);Loss of MoRF binding (P = 0.012);
MVP		0.91
MPC		1.4
ClinPred		0.96	D
GERP RS		1.7
PromoterAI		0.0055	Neutral
Varity_R		0.69
gMVP		0.94
Mutation Taster		=64/36	polymorphism

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

Other links and lift over

dbSNP: rs148830698; hg19: chr19-1207037;