rs750567076

Variant names:

• chr8-42357198-C-G
• rs750567076
• NM_002690.3:c.452C>G

Your query was ambiguous. Multiple possible variants found:

• chr8-42357198-C-G
• chr8-42357198-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002690.3(POLB):​c.452C>G​(p.Pro151Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: POLB NM_002690.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.41

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

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLB	NM_002690.3	c.452C>G	p.Pro151Arg	missense_variant	Exon 8 of 14	ENST00000265421.9	NP_002681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLB	ENST00000265421.9	c.452C>G	p.Pro151Arg	missense_variant	Exon 8 of 14	1	NM_002690.3	ENSP00000265421.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.452C>G (p.P151R) alteration is located in exon 8 (coding exon 8) of the POLB gene. This alteration results from a C to G substitution at nucleotide position 452, causing the proline (P) at amino acid position 151 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	.;T;T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.064	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.7	.;H;.
PrimateAI	Uncertain	0.79	T
PROVEAN	Pathogenic	-8.4	D;D;D
REVEL	Pathogenic	0.65
Sift	Uncertain	0.0020	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.99	.;D;.
Vest4		0.86
MutPred		0.64		.;Gain of MoRF binding (P = 0.015);.;
MVP		0.97
MPC		1.7
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.94
gMVP		0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs750567076; hg19: chr8-42214716;