dbSNP rs3136797: POLB:p.Pro242Arg (chr8-42369287-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_002690.3(POLB):c.725C>G(p.Pro242Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0152 in 1,581,432 control chromosomes in the GnomAD database, including 256 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 0.011 ( 12 hom., cov: 32)

Exomes 𝑓: 0.016 ( 244 hom. )

Consequence

POLB
NM_002690.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.48

Publications

59 publications found

Variant links:

Genes affected

POLB (HGNC:9174): (DNA polymerase beta) The protein encoded by this gene is a DNA polymerase involved in base excision and repair, also called gap-filling DNA synthesis. The encoded protein, acting as a monomer, is normally found in the cytoplasm, but it translocates to the nucleus upon DNA damage. Several transcript variants of this gene exist, but the full-length nature of only one has been described to date. [provided by RefSeq, Sep 2011]

POLB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059150755).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0105 (1600/152136) while in subpopulation NFE AF = 0.0182 (1234/67988). AF 95% confidence interval is 0.0173. There are 12 homozygotes in GnomAd4. There are 723 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLB	NM_002690.3 link	c.725C>G	p.Pro242Arg	missense_variant	Exon 12 of 14	ENST00000265421.9	NP_002681.1	P06746

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLB	ENST00000265421.9 link	c.725C>G	p.Pro242Arg	missense_variant	Exon 12 of 14	1	NM_002690.3	ENSP00000265421.4		P06746

Frequencies

GnomAD3 genomes

AF:

0.0105

AC:

1600

AN:

152018

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00275

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00642

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.0101

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0181

Gnomad OTH

AF:

0.0110

GnomAD2 exomes

AF:

0.0106

AC:

2618

AN:

247430

AF XY:

0.0103

show subpopulations

Gnomad AFR exome

AF:

0.00208

Gnomad AMR exome

AF:

0.00357

Gnomad ASJ exome

AF:

0.00319

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0133

Gnomad NFE exome

AF:

0.0175

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.0156

AC:

22359

AN:

1429296

Hom.:

244

Cov.:

AF XY:

0.0154

AC XY:

11011

AN XY:

713068

show subpopulations

African (AFR)

AF:

0.00233

AC:

AN:

32680

American (AMR)

AF:

0.00396

AC:

175

AN:

44178

Ashkenazi Jewish (ASJ)

AF:

0.00282

AC:

AN:

25876

East Asian (EAS)

AF:

0.0000510

AC:

AN:

39196

South Asian (SAS)

AF:

0.00392

AC:

333

AN:

85026

European-Finnish (FIN)

AF:

0.0139

AC:

741

AN:

53302

Middle Eastern (MID)

AF:

0.00403

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.0187

AC:

20245

AN:

1084130

Other (OTH)

AF:

0.0117

AC:

691

AN:

59200

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.427

Heterozygous variant carriers

859

1719

2578

3438

4297

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

732

1464

2196

2928

3660

<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:

0.0105

AC:

1600

AN:

152136

Hom.:

Cov.:

AF XY:

0.00972

AC XY:

723

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.00275

AC:

114

AN:

41506

American (AMR)

AF:

0.00642

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00332

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0101

AC:

107

AN:

10578

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0182

AC:

1234

AN:

67988

Other (OTH)

AF:

0.0109

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

164

246

328

410

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.0159

Hom.:

Bravo

AF:

0.00987

TwinsUK

AF:

0.0197

AC:

ALSPAC

AF:

0.0221

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0151

AC:

130

ExAC

AF:

0.0111

AC:

1341

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0144

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.35

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.40

T;T

Eigen

Benign

0.087

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.83

T;T

MetaRNN

Benign

0.0059

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

M;.

PhyloP100

4.5

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-4.1

D;D

REVEL

Benign

0.12

Sift

Benign

0.063

T;D

Sift4G

Benign

0.22

T;D

Polyphen

0.0

B;.

Vest4

0.18

MPC

0.68

ClinPred

0.039

GERP RS

5.7

PromoterAI

0.0066

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.61

Mutation Taster

=74/26

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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