8-42355555-G-A

Variant names:

• chr8-42355555-G-A
• rs12678588
• NM_002690.3:c.410G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_002690.3(POLB):​c.410G>A​(p.Arg137Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000327 in 1,591,400 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 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 0.00053 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (3 hom.)
• Consequence: POLB NM_002690.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.17
• Publications: 29 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009117395).
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002690.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLB	NM_002690.3	MANE Select	c.410G>A	p.Arg137Gln	missense	Exon 7 of 14	NP_002681.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLB	ENST00000265421.9	TSL:1 MANE Select	c.410G>A	p.Arg137Gln	missense	Exon 7 of 14	ENSP00000265421.4
	POLB	ENST00000518925.5	TSL:5	c.515G>A	p.Arg172Gln	missense	Exon 8 of 13	ENSP00000430784.1
	POLB	ENST00000521290.5	TSL:5	c.200G>A	p.Arg67Gln	missense	Exon 4 of 10	ENSP00000429597.1

Frequencies

GnomAD3 genomes AF: 0.000533 AC: 81 AN: 152094 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00616

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00138 AC: 345 AN: 250346 AF XY: 0.00110

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.00704

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000655

GnomAD4 exome AF: 0.000305 AC: 439 AN: 1439188 Hom.: 3 Cov.: 24 AF XY: 0.000275 AC XY: 197 AN XY: 717542

African (AFR) AF: 0.000212 AC: 7 AN: 33012

American (AMR) AF: 0.00623 AC: 277 AN: 44440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25918

East Asian (EAS) AF: 0.00321 AC: 127 AN: 39548

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85564

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.0000101 AC: 11 AN: 1092224

Other (OTH) AF: 0.000252 AC: 15 AN: 59512

GnomAD4 genome AF: 0.000532 AC: 81 AN: 152212 Hom.: 3 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74406

African (AFR) AF: 0.000193 AC: 8 AN: 41532

American (AMR) AF: 0.00242 AC: 37 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00618 AC: 32 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000273 Hom.: 1

Bravo AF: 0.000774

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00117 AC: 142

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.21
Eigen_PC	Benign	0.040
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.49	N
PhyloP100		4.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.047
Sift	Benign	0.20	T
Sift4G	Benign	0.50	T
Polyphen		0.010	B
Vest4		0.21
MVP		0.32
MPC		0.75
ClinPred		0.017	T
GERP RS		5.3
Varity_R		0.30
gMVP		0.57
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs12678588; hg19: chr8-42213073;