8-42361331-C-G

Variant names:

• chr8-42361331-C-G
• rs56121607
• NM_002690.3:c.587C>G

Variant summary

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

The NM_002690.3(POLB):​c.587C>G​(p.Thr196Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,612,494 control chromosomes in the GnomAD database, including 4 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 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (4 hom.)
• Consequence: POLB NM_002690.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.69
• Publications: 5 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=0.009784162).
• BS2: High Homozygotes in GnomAdExome4 at 4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLB	NM_002690.3	MANE Select	c.587C>G	p.Thr196Ser	missense	Exon 10 of 14	NP_002681.1	P06746

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLB	ENST00000265421.9	TSL:1 MANE Select	c.587C>G	p.Thr196Ser	missense	Exon 10 of 14	ENSP00000265421.4	P06746
	POLB	ENST00000929417.1		c.587C>G	p.Thr196Ser	missense	Exon 10 of 14	ENSP00000599476.1
	POLB	ENST00000518925.5	TSL:5	c.692C>G	p.Thr231Ser	missense	Exon 11 of 13	ENSP00000430784.1	E7EW18

Frequencies

GnomAD3 genomes AF: 0.000375 AC: 57 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00980

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000740 AC: 186 AN: 251468 AF XY: 0.000684

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00962

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000269 AC: 393 AN: 1460208 Hom.: 4 Cov.: 28 AF XY: 0.000259 AC XY: 188 AN XY: 726546

African (AFR) AF: 0.00 AC: 0 AN: 33446

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00910 AC: 361 AN: 39684

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110508

Other (OTH) AF: 0.000282 AC: 17 AN: 60332

GnomAD4 genome AF: 0.000374 AC: 57 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.000537 AC XY: 40 AN XY: 74456

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.000131 AC: 2 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00982 AC: 51 AN: 5194

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2108

Alfa AF: 0.000360 Hom.: 0

Bravo AF: 0.000499

ExAC AF: 0.000749 AC: 91

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.016
Eigen_PC	Benign	0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		7.7
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.16
Sift	Benign	0.17	T
Sift4G	Benign	0.20	T
Polyphen		0.068	B
Vest4		0.83
MutPred		0.56		Gain of disorder (P = 0.0295)
MVP		0.27
MPC		0.74
ClinPred		0.081	T
GERP RS		5.6
PromoterAI		-0.0045	Neutral
Varity_R		0.64
gMVP		0.64
Mutation Taster		=75/25	polymorphism

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

Other links and lift over

dbSNP: rs56121607; hg19: chr8-42218849;