chr19-1219380-C-A

Variant names:

• chr19-1219380-C-A
• rs1006375117
• NM_000455.5:c.431C>A

Variant summary

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

The NM_000455.5(STK11):​c.431C>A​(p.Pro144Gln) variant causes a missense change. 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. P144L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.79
• 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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 42 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.431C>A	p.Pro144Gln	missense_variant	Exon 3 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.431C>A	p.Pro144Gln	missense_variant	Exon 3 of 9		NP_001394184.1
STK11	NR_176325.1	n.1698C>A		non_coding_transcript_exon_variant	Exon 4 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STK11	ENST00000326873.12	c.431C>A	p.Pro144Gln	missense_variant	Exon 3 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.431C>A	p.Pro144Gln	missense_variant	Exon 3 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.59C>A	p.Pro20Gln	missense_variant	Exon 5 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*256C>A		non_coding_transcript_exon_variant	Exon 4 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*256C>A		3_prime_UTR_variant	Exon 4 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1350360 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 669944

African (AFR) AF: 0.00 AC: 0 AN: 30224

American (AMR) AF: 0.00 AC: 0 AN: 39898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22178

East Asian (EAS) AF: 0.00 AC: 0 AN: 23010

South Asian (SAS) AF: 0.00 AC: 0 AN: 82398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42808

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5148

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1051484

Other (OTH) AF: 0.00 AC: 0 AN: 53212

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.31	.;T;D
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.055
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.82	T;D;D
M_CAP	Benign	0.040	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.1	.;.;L
PhyloP100		5.8
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.3	.;.;D
REVEL	Benign	0.19
Sift	Benign	0.048	.;.;D
Sift4G	Benign	0.085	.;T;T
Polyphen		0.27	.;.;B
Vest4		0.55, 0.59
MutPred		0.50		.;Gain of ubiquitination at K146 (P = 0.1162);Gain of ubiquitination at K146 (P = 0.1162);
MVP		0.56
MPC		0.94
ClinPred		0.92	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.51
gMVP		0.61
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs1006375117; hg19: chr19-1219379;