Genetic Variant POLK:p.Ala309Ala (chr5-75581441-C-T) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The ENST00000241436.9(POLK):c.927C>T(p.Ala309Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.225 in 1,610,014 control chromosomes in the GnomAD database, including 43,187 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 0.22 ( 3906 hom., cov: 32)

Exomes 𝑓: 0.22 ( 39281 hom. )

Consequence

POLK
ENST00000241436.9 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.773

Publications

24 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28).

BP7

Synonymous conserved (PhyloP=0.773 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.38 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	Protein
POLK	NM_001387111.3 link	c.969C>T	p.Ala323Ala	synonymous_variant	Exon 8 of 16	NP_001374040.1
POLK	NM_001395894.1 link	c.969C>T	p.Ala323Ala	synonymous_variant	Exon 9 of 17	NP_001382823.1
POLK	NM_001395897.1 link	c.966C>T	p.Ala322Ala	synonymous_variant	Exon 8 of 16	NP_001382826.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLK	ENST00000241436.9 link	c.927C>T	p.Ala309Ala	synonymous_variant	Exon 7 of 15	1		ENSP00000241436.4		Q9UBT6-1

Frequencies

GnomAD3 genomes

AF:

0.222

AC:

33803

AN:

151942

Hom.:

3901

Cov.:

show subpopulations

Gnomad AFR

AF:

0.218

Gnomad AMI

AF:

0.281

Gnomad AMR

AF:

0.186

Gnomad ASJ

AF:

0.267

Gnomad EAS

AF:

0.324

Gnomad SAS

AF:

0.394

Gnomad FIN

AF:

0.234

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.209

Gnomad OTH

AF:

0.219

GnomAD2 exomes

AF:

0.237

AC:

59418

AN:

250182

AF XY:

0.247

show subpopulations

Gnomad AFR exome

AF:

0.220

Gnomad AMR exome

AF:

0.146

Gnomad ASJ exome

AF:

0.265

Gnomad EAS exome

AF:

0.322

Gnomad FIN exome

AF:

0.235

Gnomad NFE exome

AF:

0.211

Gnomad OTH exome

AF:

0.230

GnomAD4 exome

AF:

0.225

AC:

328007

AN:

1457954

Hom.:

39281

Cov.:

AF XY:

0.231

AC XY:

167292

AN XY:

725558

show subpopulations

African (AFR)

AF:

0.223

AC:

7440

AN:

33400

American (AMR)

AF:

0.151

AC:

6737

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.265

AC:

6903

AN:

26090

East Asian (EAS)

AF:

0.338

AC:

13408

AN:

39646

South Asian (SAS)

AF:

0.389

AC:

33524

AN:

86130

European-Finnish (FIN)

AF:

0.234

AC:

12509

AN:

53404

Middle Eastern (MID)

AF:

0.277

AC:

1596

AN:

5760

European-Non Finnish (NFE)

AF:

0.209

AC:

232158

AN:

1108532

Other (OTH)

AF:

0.228

AC:

13732

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

11283

22566

33849

45132

56415

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8210

16420

24630

32840

41050

<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:

0.222

AC:

33828

AN:

152060

Hom.:

3906

Cov.:

AF XY:

0.227

AC XY:

16889

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.219

AC:

9066

AN:

41484

American (AMR)

AF:

0.186

AC:

2839

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

925

AN:

3468

East Asian (EAS)

AF:

0.324

AC:

1671

AN:

5158

South Asian (SAS)

AF:

0.395

AC:

1902

AN:

4812

European-Finnish (FIN)

AF:

0.234

AC:

2474

AN:

10556

Middle Eastern (MID)

AF:

0.197

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.209

AC:

14182

AN:

67982

Other (OTH)

AF:

0.216

AC:

456

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1324

2648

3971

5295

6619

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

372

744

1116

1488

1860

<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:

0.215

Hom.:

7121

Bravo

AF:

0.215

Asia WGS

AF:

0.335

AC:

1163

AN:

3478

EpiCase

AF:

0.218

EpiControl

AF:

0.214

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.76

PhyloP100

0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=93/7

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over