NM_005030.6:c.1496C>A

Variant names:

• chr16-23689564-C-A
• rs138397393
• NM_005030.6:c.1496C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005030.6(PLK1):​c.1496C>A​(p.Pro499Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign 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. P499L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PLK1 NM_005030.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.67
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3098389).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005030.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLK1	NM_005030.6	MANE Select	c.1496C>A	p.Pro499Gln	missense	Exon 9 of 10	NP_005021.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PLK1	ENST00000300093.9	TSL:1 MANE Select	c.1496C>A	p.Pro499Gln	missense	Exon 9 of 10	ENSP00000300093.4	P53350
	PLK1	ENST00000885692.1		c.1463C>A	p.Pro488Gln	missense	Exon 9 of 10	ENSP00000555751.1
	PLK1	ENST00000922967.1		c.1037C>A	p.Pro346Gln	missense	Exon 6 of 7	ENSP00000593026.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461382 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726972

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53074

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.045	D
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.6	L
PhyloP100		5.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.10
Sift	Benign	0.29	T
Sift4G	Benign	0.21	T
Polyphen		0.28	B
Vest4		0.48
MutPred		0.34		Loss of catalytic residue at P499 (P = 0.0489)
MVP		0.49
MPC		0.75
ClinPred		0.73	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.41
gMVP		0.35

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: rs138397393; hg19: chr16-23700885;