rs148960463

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP2BP4_StrongBS1_SupportingBS2

The NM_001387111.3(POLK):c.85G>A(p.Glu29Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00197 in 1,540,640 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0020 ( 7 hom. )

Consequence

POLK
NM_001387111.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:1

Conservation

PhyloP100: 5.07

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 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=0.010744542).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00141 (215/152288) while in subpopulation SAS AF = 0.00456 (22/4824). AF 95% confidence interval is 0.00309. There are 0 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
POLK	NM_001387111.3 link	c.85G>A	p.Glu29Lys	missense_variant	Exon 2 of 16	NP_001374040.1
POLK	NM_001395894.1 link	c.85G>A	p.Glu29Lys	missense_variant	Exon 3 of 17	NP_001382823.1
POLK	NM_001395897.1 link	c.85G>A	p.Glu29Lys	missense_variant	Exon 3 of 16	NP_001382826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLK	ENST00000241436.9 link	c.85G>A	p.Glu29Lys	missense_variant	Exon 2 of 15	1		ENSP00000241436.4		Q9UBT6-1

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

215

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00456

Gnomad FIN

AF:

0.000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00228

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00210

AC:

498

AN:

236644

AF XY:

0.00239

show subpopulations

Gnomad AFR exome

AF:

0.000336

Gnomad AMR exome

AF:

0.000999

Gnomad ASJ exome

AF:

0.000408

Gnomad EAS exome

AF:

0.0000599

Gnomad FIN exome

AF:

0.00116

Gnomad NFE exome

AF:

0.00261

Gnomad OTH exome

AF:

0.00178

GnomAD4 exome

AF:

0.00204

AC:

2826

AN:

1388352

Hom.:

Cov.:

AF XY:

0.00213

AC XY:

1477

AN XY:

692942

show subpopulations

Gnomad4 AFR exome

AF:

0.000255

AC:

AN:

31368

Gnomad4 AMR exome

AF:

0.00114

AC:

AN:

42046

Gnomad4 ASJ exome

AF:

0.000753

AC:

AN:

25234

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

37698

Gnomad4 SAS exome

AF:

0.00516

AC:

414

AN:

80292

Gnomad4 FIN exome

AF:

0.00108

AC:

AN:

52714

Gnomad4 NFE exome

AF:

0.00207

AC:

2181

AN:

1055840

Gnomad4 Remaining exome

AF:

0.00151

AC:

AN:

57688

Heterozygous variant carriers

112

224

336

448

560

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

156

234

312

390

<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:

0.00141

AC:

215

AN:

152288

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000289

AC:

0.000288684

AN:

0.000288684

Gnomad4 AMR

AF:

0.000392

AC:

0.000392259

AN:

0.000392259

Gnomad4 ASJ

AF:

0.000864

AC:

0.000864055

AN:

0.000864055

Gnomad4 EAS

AF:

0.000386

AC:

0.0003861

AN:

0.0003861

Gnomad4 SAS

AF:

0.00456

AC:

0.00456053

AN:

0.00456053

Gnomad4 FIN

AF:

0.000942

AC:

0.000942152

AN:

0.000942152

Gnomad4 NFE

AF:

0.00228

AC:

0.00227901

AN:

0.00227901

Gnomad4 OTH

AF:

0.00189

AC:

0.00189036

AN:

0.00189036

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

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:

0.00219

Hom.:

Bravo

AF:

0.00112

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00198

AC:

ExAC

AF:

0.00219

AC:

266

Asia WGS

AF:

0.00202

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Prostate cancer

Pathogenic:1

Nov 06, 2013

Tulane Cancer Center, Tulane University

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

- -

Seizure;C4022738:Neurodevelopmental delay

Benign:1

Feb 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.20

T;T;.;.;.

Eigen

Uncertain

0.58

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;D;D;D;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.011

T;T;T;T;T

MetaSVM

Benign

-0.53

MutationAssessor

Uncertain

2.0

M;.;M;M;M

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-2.3

N;D;N;N;N

REVEL

Benign

0.17

Sift

Uncertain

0.027

D;T;T;T;T

Sift4G

Uncertain

0.060

T;D;T;T;T

Polyphen

0.96

D;.;P;.;P

Vest4

0.31

MVP

0.64

MPC

0.13

ClinPred

0.74

GERP RS

5.6

Varity_R

0.75

gMVP

0.27

Mutation Taster

=265/35

disease causing (ClinVar)

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over