Genetic Variant POLK:p.Leu731Pro (chr5-75596885-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM2PM5PP2BP4_Moderate

The NM_016218.6(POLK):c.2192T>C(p.Leu731Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 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. L731H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

POLK
NM_016218.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.312

Publications

0 publications found

Variant links:

Genes affected

POLK (HGNC:9183): (DNA polymerase kappa) This gene encodes a member of the DNA polymerase type-Y family of proteins. The encoded protein is a specialized DNA polymerase that catalyzes translesion DNA synthesis, which allows DNA replication in the presence of DNA lesions. Human cell lines lacking a functional copy of this gene exhibit impaired genome integrity and enhanced susceptibility to oxidative damage. Mutations in this gene that impair enzyme activity may be associated with prostate cancer in human patients. [provided by RefSeq, Sep 2016]

POLK links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-75596885-T-A is described in ClinVar as Pathogenic. ClinVar VariationId is 218223.Status of the report is criteria_provided_single_submitter, 1 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 14 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.28752 (below the threshold of 3.09). Trascript score misZ: 0.94642 (below the threshold of 3.09).

BP4

Computational evidence support a benign effect (MetaRNN=0.19417855).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016218.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLK	NM_016218.6	MANE Select	c.2192T>C	p.Leu731Pro	missense	Exon 13 of 15	NP_057302.1	Q9UBT6-1
POLK	NM_001387111.3		c.2234T>C	p.Leu745Pro	missense	Exon 14 of 16	NP_001374040.1
POLK	NM_001395894.1		c.2234T>C	p.Leu745Pro	missense	Exon 15 of 17	NP_001382823.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLK	ENST00000241436.9	TSL:1 MANE Select	c.2192T>C	p.Leu731Pro	missense	Exon 13 of 15	ENSP00000241436.4	Q9UBT6-1
POLK	ENST00000508526.5	TSL:1	c.1598T>C	p.Leu533Pro	missense	Exon 7 of 9	ENSP00000426853.1	Q9UBT6-3
POLK	ENST00000504026.5	TSL:1	c.1357-862T>C		intron	N/A	ENSP00000425075.1	Q9UBT6-6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.097

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.55

M_CAP

Benign

0.022

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.4

PhyloP100

0.31

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.4

REVEL

Benign

0.15

Sift

Benign

0.15

Sift4G

Benign

0.32

Polyphen

0.97

Vest4

0.27

MutPred

0.20

Gain of glycosylation at L731 (P = 0.0131)

MVP

0.71

MPC

0.37

ClinPred

0.63

GERP RS

3.1

Varity_R

0.14

gMVP

0.37

Mutation Taster

=46/54

disease causing

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over