Genetic Variant POLK:p.Ile612Val (chr5-75596527-A-G) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2BP4_StrongBS1BS2

The NM_016218.6(POLK):c.1834A>G(p.Ile612Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000933 in 1,614,018 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0021 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00081 ( 9 hom. )

Consequence

POLK
NM_016218.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.313

Publications

5 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: Benign. The variant received -11 ACMG points.

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=0.002148807).

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00208 (317/152344) while in subpopulation EAS AF = 0.0274 (142/5186). AF 95% confidence interval is 0.0237. There are 1 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

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
POLK	NM_016218.6	MANE Select	c.1834A>G	p.Ile612Val	missense	Exon 13 of 15	NP_057302.1
POLK	NM_001387111.3		c.1876A>G	p.Ile626Val	missense	Exon 14 of 16	NP_001374040.1
POLK	NM_001395894.1		c.1876A>G	p.Ile626Val	missense	Exon 15 of 17	NP_001382823.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
POLK	ENST00000241436.9	TSL:1 MANE Select	c.1834A>G	p.Ile612Val	missense	Exon 13 of 15	ENSP00000241436.4
POLK	ENST00000508526.5	TSL:1	c.1240A>G	p.Ile414Val	missense	Exon 7 of 9	ENSP00000426853.1
POLK	ENST00000514141.5	TSL:1	n.*453A>G		non_coding_transcript_exon	Exon 11 of 13	ENSP00000423526.1

Frequencies

GnomAD3 genomes

AF:

0.00208

AC:

317

AN:

152224

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00367

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0273

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00253

AC:

632

AN:

249636

AF XY:

0.00226

show subpopulations

Gnomad AFR exome

AF:

0.00373

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0292

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.000824

GnomAD4 exome

AF:

0.000813

AC:

1189

AN:

1461674

Hom.:

Cov.:

AF XY:

0.000785

AC XY:

571

AN XY:

727142

show subpopulations

African (AFR)

AF:

0.00418

AC:

140

AN:

33478

American (AMR)

AF:

0.000268

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.0199

AC:

789

AN:

39682

South Asian (SAS)

AF:

0.000800

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.0000188

AC:

AN:

53308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000216

AC:

AN:

1111944

Other (OTH)

AF:

0.00255

AC:

154

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

160

241

321

401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00208

AC:

317

AN:

152344

Hom.:

Cov.:

AF XY:

0.00199

AC XY:

148

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.00365

AC:

152

AN:

41592

American (AMR)

AF:

0.000523

AC:

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.0274

AC:

142

AN:

5186

South Asian (SAS)

AF:

0.00186

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68014

Other (OTH)

AF:

0.00142

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.00237

ESP6500AA

AF:

0.00295

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00240

AC:

291

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.60

CADD

Benign

7.5

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.026

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.78

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.44

MetaRNN

Benign

0.0021

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

0.31

PrimateAI

Benign

0.28

PROVEAN

Benign

0.17

REVEL

Benign

0.027

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.053

MVP

0.34

MPC

0.060

ClinPred

0.0075

GERP RS

3.0

Varity_R

0.020

gMVP

0.094

Mutation Taster

=99/1

polymorphism

(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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over