14-49647325-A-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_002692.4(POLE2):​c.1533T>G​(p.Val511Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000464 in 1,576,916 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00059 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (3 hom.)
• Consequence: POLE2 NM_002692.4 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 14-49647325-A-C is Benign according to our data. Variant chr14-49647325-A-C is described in ClinVar as Benign. ClinVar VariationId is 1642534.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.162 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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>G	p.Val511Val	synonymous	Exon 18 of 19	NP_002683.2
	POLE2	NM_001348384.2		c.1530T>G	p.Val510Val	synonymous	Exon 18 of 19	NP_001335313.1
	POLE2	NM_001197330.2		c.1455T>G	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>G	p.Val511Val	synonymous	Exon 18 of 19	ENSP00000216367.5	P56282-1
	POLE2	ENST00000539565.6	TSL:1	c.1455T>G	p.Val485Val	synonymous	Exon 17 of 18	ENSP00000446313.2	P56282-2
	POLE2	ENST00000960548.1		c.1455T>G	p.Val485Val	synonymous	Exon 17 of 18	ENSP00000630607.1

Frequencies

GnomAD3 genomes AF: 0.000591 AC: 90 AN: 152240 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00443

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000617

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000660 AC: 155 AN: 234834 AF XY: 0.000595

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000663

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00415

Gnomad NFE exome AF: 0.000562

Gnomad OTH exome AF: 0.000545

GnomAD4 exome AF: 0.000450 AC: 641 AN: 1424676 Hom.: 3 Cov.: 25 AF XY: 0.000450 AC XY: 319 AN XY: 709304

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

American (AMR) AF: 0.0000731 AC: 3 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: 0.00570 AC: 301 AN: 52762

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

European-Non Finnish (NFE) AF: 0.000282 AC: 307 AN: 1090080

Other (OTH) AF: 0.000509 AC: 30 AN: 58886

GnomAD4 genome AF: 0.000591 AC: 90 AN: 152240 Hom.: 1 Cov.: 32 AF XY: 0.000645 AC XY: 48 AN XY: 74384

African (AFR) AF: 0.0000241 AC: 1 AN: 41470

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00443 AC: 47 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000617 AC: 42 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000731 Hom.: 0

Bravo AF: 0.000136

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	10
DANN	Benign	0.69
PhyloP100		-0.16
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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;