chr19-1221961-A-C

Variant names:

• chr19-1221961-A-C
• rs587780011
• NM_000455.5:c.875A>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.875A>C​(p.Tyr292Ser) 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. Y292C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 34)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.60
• 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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 28 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.875A>C	p.Tyr292Ser	missense_variant	Exon 7 of 10	ENST00000326873.12	NP_000446.1
STK11	NM_001407255.1	c.875A>C	p.Tyr292Ser	missense_variant	Exon 7 of 9		NP_001394184.1
STK11	NR_176325.1	n.2142A>C		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.875A>C	p.Tyr292Ser	missense_variant	Exon 7 of 10	1	NM_000455.5	ENSP00000324856.6
STK11	ENST00000652231.1	c.875A>C	p.Tyr292Ser	missense_variant	Exon 7 of 9			ENSP00000498804.1
STK11	ENST00000585748.3	c.503A>C	p.Tyr168Ser	missense_variant	Exon 9 of 12	3		ENSP00000477641.2
STK11	ENST00000593219.6	n.*700A>C		non_coding_transcript_exon_variant	Exon 8 of 11	3		ENSP00000466610.1
STK11	ENST00000593219.6	n.*700A>C		3_prime_UTR_variant	Exon 8 of 11	3		ENSP00000466610.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.20
CADD	Uncertain	24
DANN	Benign	0.83
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.53	D;D
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.23	.;N
PhyloP100		5.6
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.47	.;N
REVEL	Uncertain	0.58
Sift	Benign	0.39	.;T
Sift4G	Benign	0.45	T;T
Polyphen		0.51	.;P
Vest4		0.62
MutPred		0.49		Gain of disorder (P = 0.0023);Gain of disorder (P = 0.0023);
MVP		0.97
MPC		0.31
ClinPred		0.62	D
GERP RS		3.6
Varity_R		0.36
gMVP		0.87
Mutation Taster		=71/29	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: rs587780011; hg19: chr19-1221960;