8-42369304-A-G

Position:

• chr8-42369304-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002690.3(POLB):​c.742A>G​(p.Lys248Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000139 in 1,442,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLB NM_002690.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.38

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08350581).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLB	NM_002690.3	c.742A>G	p.Lys248Glu	missense_variant	12/14	ENST00000265421.9	NP_002681.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLB	ENST00000265421.9	c.742A>G	p.Lys248Glu	missense_variant	12/14	1	NM_002690.3	ENSP00000265421	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000139 AC: 2 AN: 1442830 Hom.: 0 Cov.: 25 AF XY: 0.00000278 AC XY: 2 AN XY: 719136

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000451

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.742A>G (p.K248E) alteration is located in exon 12 (coding exon 12) of the POLB gene. This alteration results from a A to G substitution at nucleotide position 742, causing the lysine (K) at amino acid position 248 to be replaced by a glutamic acid (E). 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	Benign	0.075
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.019
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.47	N
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.080	N
REVEL	Benign	0.11
Sift	Benign	0.61	T
Sift4G	Benign	0.88	T
Polyphen		0.0	B
Vest4		0.20
MutPred		0.34		Loss of ubiquitination at K248 (P = 0.011);
MVP		0.34
MPC		0.89
ClinPred		0.086	T
GERP RS		4.2
Varity_R		0.22
gMVP		0.38

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

LitVar

Other links and lift over

dbSNP: rs1354301189; hg19: chr8-42226822;