rs1060499967

Variant names:

• chr19-1223139-G-A
• rs1060499967
• NM_000455.5:c.1075G>A

Your query was ambiguous. Multiple possible variants found:

• chr19-1223139-G-A
• chr19-1223139-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000455.5(STK11):​c.1075G>A​(p.Asp359Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D359E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: STK11 NM_000455.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.38
• Publications: 3 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.23684078).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000455.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	NM_000455.5	MANE Select	c.1075G>A	p.Asp359Asn	missense	Exon 8 of 10	NP_000446.1
	STK11	NM_001407255.1		c.1075G>A	p.Asp359Asn	missense	Exon 8 of 9	NP_001394184.1
	STK11	NR_176325.1		n.2342G>A		non_coding_transcript_exon	Exon 9 of 11

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	STK11	ENST00000326873.12	TSL:1 MANE Select	c.1075G>A	p.Asp359Asn	missense	Exon 8 of 10	ENSP00000324856.6
	STK11	ENST00000652231.1		c.1075G>A	p.Asp359Asn	missense	Exon 8 of 9	ENSP00000498804.1
	STK11	ENST00000585748.3	TSL:3	c.703G>A	p.Asp235Asn	missense	Exon 10 of 12	ENSP00000477641.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459554 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 725932

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26098

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111548

Other (OTH) AF: 0.00 AC: 0 AN: 60320

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Melanoma, cutaneous malignant, susceptibility to, 1 (1)
-	1	-	Peutz-Jeghers syndrome (1)
-	1	-	STK11-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.4	L
PhyloP100		7.4
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.21
Sift	Benign	0.22	T
Sift4G	Benign	0.32	T
Polyphen		0.0	B
Vest4		0.28
MutPred		0.45		Loss of stability (P = 0.1038)
MVP		0.51
MPC		0.041
ClinPred		0.83	D
GERP RS		2.8
PromoterAI		-0.094	Neutral
Varity_R		0.090
gMVP		0.24
Mutation Taster		=81/19	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: rs1060499967; hg19: chr19-1223138;