chr14-49643675-A-T

Variant names:

• chr14-49643675-A-T
• NM_002692.4:c.1566-5T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002692.4(POLE2):​c.1566-5T>A variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: POLE2 NM_002692.4 splice_region, intron
• Scores: Splicing: ADA: 0.1441
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.22
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).

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.1566-5T>A		splice_region intron	N/A	NP_002683.2
	POLE2	NM_001348384.2		c.1563-5T>A		splice_region intron	N/A	NP_001335313.1
	POLE2	NM_001197330.2		c.1488-5T>A		splice_region intron	N/A	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.1566-5T>A		splice_region intron	N/A	ENSP00000216367.5	P56282-1
	POLE2	ENST00000539565.6	TSL:1	c.1488-5T>A		splice_region intron	N/A	ENSP00000446313.2	P56282-2
	POLE2	ENST00000960548.1		c.1488-5T>A		splice_region intron	N/A	ENSP00000630607.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 19

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	-0.30
CADD	Benign	16
DANN	Benign	0.94
PhyloP100		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.14
dbscSNV1_RF	Benign	0.47
SpliceAI score (max)		0.52		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.52		Position offset: -5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr14-50110393;