dbSNP rs35257416: POLK:p.Ser423Arg (chr5-75590351-A-C) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 3P and 12B. PM1PP2BP4_StrongBS1BS2

The ENST00000241436.9(POLK):c.1267A>C(p.Ser423Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00087 in 1,573,402 control chromosomes in the GnomAD database, including 14 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.

Frequency

Genomes: 𝑓 0.0046 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 9 hom. )

Consequence

POLK
ENST00000241436.9 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.73

Publications

7 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000241436.9

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=0.009204656).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00465 (708/152316) while in subpopulation AFR AF = 0.0162 (675/41568). AF 95% confidence interval is 0.0152. There are 5 homozygotes in GnomAd4. There are 321 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
POLK	NM_001387111.3 link	c.1309A>C	p.Ser437Arg	missense_variant	Exon 12 of 16	NP_001374040.1
POLK	NM_001395894.1 link	c.1309A>C	p.Ser437Arg	missense_variant	Exon 13 of 17	NP_001382823.1
POLK	NM_001395897.1 link	c.1306A>C	p.Ser436Arg	missense_variant	Exon 12 of 16	NP_001382826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLK	ENST00000241436.9 link	c.1267A>C	p.Ser423Arg	missense_variant	Exon 11 of 15	1		ENSP00000241436.4		Q9UBT6-1

Frequencies

GnomAD3 genomes

AF:

0.00465

AC:

707

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00383

GnomAD2 exomes

AF:

0.00130

AC:

312

AN:

239804

AF XY:

0.000877

show subpopulations

Gnomad AFR exome

AF:

0.0173

Gnomad AMR exome

AF:

0.000900

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000182

Gnomad OTH exome

AF:

0.000518

GnomAD4 exome

AF:

0.000465

AC:

661

AN:

1421086

Hom.:

Cov.:

AF XY:

0.000417

AC XY:

295

AN XY:

707390

show subpopulations

African (AFR)

AF:

0.0159

AC:

512

AN:

32270

American (AMR)

AF:

0.00110

AC:

AN:

41086

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25000

East Asian (EAS)

AF:

0.00

AC:

AN:

39368

South Asian (SAS)

AF:

0.000135

AC:

AN:

81766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52448

Middle Eastern (MID)

AF:

0.00142

AC:

AN:

5618

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

1084860

Other (OTH)

AF:

0.00124

AC:

AN:

58670

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00465

AC:

708

AN:

152316

Hom.:

Cov.:

AF XY:

0.00431

AC XY:

321

AN XY:

74486

show subpopulations

African (AFR)

AF:

0.0162

AC:

675

AN:

41568

American (AMR)

AF:

0.00137

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68014

Other (OTH)

AF:

0.00379

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

101

135

169

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:

0.00251

Hom.:

Bravo

AF:

0.00553

ESP6500AA

AF:

0.0186

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00174

AC:

211

Asia WGS

AF:

0.00145

AC:

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.18

T;.;.

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

D;D;D

MetaRNN

Benign

0.0092

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

L;L;L

PhyloP100

5.7

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.3

N;N;N

REVEL

Benign

0.058

Sift

Benign

0.040

D;T;T

Sift4G

Benign

0.19

T;T;T

Polyphen

0.93

P;P;.

Vest4

0.47

MutPred

0.16

Loss of phosphorylation at S423 (P = 0.0313);Loss of phosphorylation at S423 (P = 0.0313);Loss of phosphorylation at S423 (P = 0.0313);

MVP

0.51

MPC

0.15

ClinPred

0.028

GERP RS

5.4

Varity_R

0.35

gMVP

0.27

Mutation Taster

=78/22

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over