14-49647325-A-G

Variant names:

• chr14-49647325-A-G
• rs149157567
• NM_002692.4:c.1533T>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_002692.4(POLE2):​c.1533T>C​(p.Val511Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,680 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. V511V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: POLE2 NM_002692.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.162
• Publications: 0 publications found

Genes affected

POLE2 (HGNC:9178): (DNA polymerase epsilon 2, accessory subunit) DNA polymerase epsilon, which is involved in DNA repair and replication, is composed of a large catalytic subunit and a small accessory subunit. The protein encoded by this gene represents the small subunit (B). Defects in this gene have been linked to colorectal cancer and to combined immunodeficiency. [provided by RefSeq, Jan 2017]

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP7: Synonymous conserved (PhyloP=-0.162 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002692.4. 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
	POLE2	NM_002692.4	MANE Select	c.1533T>C	p.Val511Val	synonymous	Exon 18 of 19	NP_002683.2
	POLE2	NM_001348384.2		c.1530T>C	p.Val510Val	synonymous	Exon 18 of 19	NP_001335313.1
	POLE2	NM_001197330.2		c.1455T>C	p.Val485Val	synonymous	Exon 17 of 18	NP_001184259.1	P56282-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLE2	ENST00000216367.10	TSL:1 MANE Select	c.1533T>C	p.Val511Val	synonymous	Exon 18 of 19	ENSP00000216367.5	P56282-1
	POLE2	ENST00000539565.6	TSL:1	c.1455T>C	p.Val485Val	synonymous	Exon 17 of 18	ENSP00000446313.2	P56282-2
	POLE2	ENST00000960548.1		c.1455T>C	p.Val485Val	synonymous	Exon 17 of 18	ENSP00000630607.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424680 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 709306

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31966

American (AMR) AF: 0.00 AC: 0 AN: 41058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25426

East Asian (EAS) AF: 0.00 AC: 0 AN: 37740

South Asian (SAS) AF: 0.00 AC: 0 AN: 81182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 9.17e-7 AC: 1 AN: 1090084

Other (OTH) AF: 0.00 AC: 0 AN: 58886

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.4
DANN	Benign	0.69
PhyloP100		-0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs149157567; hg19: chr14-50114043;