19-1220630-C-G

Variant names:

• chr19-1220630-C-G
• rs1057520017
• NM_000455.5:c.647C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_000455.5(STK11):​c.647C>G​(p.Ser216Cys) 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. S216F) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.80
• 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a domain Protein kinase (size 260) in uniprot entity STK11_HUMAN there are 56 pathogenic changes around while only 19 benign (75%) in NM_000455.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STK11	NM_000455.5	c.647C>G	p.Ser216Cys	missense_variant	Exon 5 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.647C>G	p.Ser216Cys	missense_variant	Exon 5 of 9		NP_001394184.1
STK11	NR_176325.1	n.1914C>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.647C>G	p.Ser216Cys	missense_variant	Exon 5 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.647C>G	p.Ser216Cys	missense_variant	Exon 5 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.275C>G	p.Ser92Cys	missense_variant	Exon 7 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*472C>G		non_coding_transcript_exon_variant	Exon 6 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*472C>G		3_prime_UTR_variant	Exon 6 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.34	T;D
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.93	D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.5	.;M
PhyloP100		7.8
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.6	.;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0010	.;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	.;D
Vest4		0.89
MutPred		0.73		Loss of disorder (P = 7e-04);Loss of disorder (P = 7e-04);
MVP		0.90
MPC		2.1
ClinPred		1.0	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.92
gMVP		0.97
Mutation Taster		=30/70	disease causing

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: rs1057520017; hg19: chr19-1220629;