rs45569335

Positions:

• chr16-23689355-T-A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 1P and 8B. PP2 BP4_Strong BS2

The NM_005030.6(PLK1):​c.1388T>A​(p.Leu463His) variant causes a missense change. The variant allele was found at a frequency of 0.00963 in 1,612,956 control chromosomes in the GnomAD database, including 99 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0065 (4 hom., cov: 32)
  • Exomes 𝑓: 0.010 (95 hom.)
• Consequence: PLK1 NM_005030.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.59

Genes affected

PLK1 (HGNC:9077): (polo like kinase 1) The Ser/Thr protein kinase encoded by this gene belongs to the CDC5/Polo subfamily. It is highly expressed during mitosis and elevated levels are found in many different types of cancer. Depletion of this protein in cancer cells dramatically inhibited cell proliferation and induced apoptosis; hence, it is a target for cancer therapy. [provided by RefSeq, Sep 2015]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP2: Missense variant where missense usually causes diseases, PLK1
• BP4: Computational evidence support a benign effect (MetaRNN=0.008825004).
• BS2: High AC in GnomAd4 at 987 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PLK1	NM_005030.6	c.1388T>A	p.Leu463His	missense_variant	8/10	ENST00000300093.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PLK1	ENST00000300093.9	c.1388T>A	p.Leu463His	missense_variant	8/10	1	NM_005030.6	P1
PLK1	ENST00000562272.5	n.3408T>A		non_coding_transcript_exon_variant	7/9	2
PLK1	ENST00000564794.1	n.188T>A		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes AF: 0.00649 AC: 987 AN: 152152 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00641

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00160

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0112

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00609 AC: 1531 AN: 251382 Hom.: 14 AF XY: 0.00599 AC XY: 814 AN XY: 135860

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00425

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00203

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.00554

GnomAD4 exome AF: 0.00995 AC: 14540 AN: 1460686 Hom.: 95 Cov.: 32 AF XY: 0.00959 AC XY: 6968 AN XY: 726390

Gnomad4 AFR exome AF: 0.00158

Gnomad4 AMR exome AF: 0.00465

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000429

Gnomad4 FIN exome AF: 0.00253

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.00663

GnomAD4 genome AF: 0.00648 AC: 987 AN: 152270 Hom.: 4 Cov.: 32 AF XY: 0.00600 AC XY: 447 AN XY: 74452

Gnomad4 AFR AF: 0.00231

Gnomad4 AMR AF: 0.00641

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00160

Gnomad4 NFE AF: 0.0112

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00919 Hom.: 4

Bravo AF: 0.00693

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0125 AC: 48

ESP6500AA AF: 0.00341 AC: 15

ESP6500EA AF: 0.0100 AC: 86

ExAC AF: 0.00630 AC: 765

Asia WGS AF: 0.000866 AC: 4 AN: 3478

EpiCase AF: 0.00867

EpiControl AF: 0.00806

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	22
DANN	Benign	0.92
DEOGEN2	Benign	0.044	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.031
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0088	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.050	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.24
Sift	Benign	0.21	T
Sift4G	Benign	0.21	T
Polyphen		0.0010	B
Vest4		0.53
MVP		0.82
MPC		1.0
ClinPred		0.018	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.62
gMVP		0.63

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs45569335; hg19: chr16-23700676; COSMIC: COSV99892663; COSMIC: COSV99892663;