Genetic Variant POLDIP2:c.993-8G>A (chr17-28348239-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_015584.5(POLDIP2):c.993-8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,600,760 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 4 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 55 hom. )

Consequence

POLDIP2
NM_015584.5 splice_region, intron

Scores

Splicing: ADA: 0.00003643

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.0370

Variant links:

Genes affected

POLDIP2 (HGNC:23781): (DNA polymerase delta interacting protein 2) This gene encodes a protein that interacts with the DNA polymerase delta p50 subunit, as well as with proliferating cell nuclear antigen. The encoded protein maybe play a role in the ability of the replication fork to bypass DNA lesions. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

POLDIP2 links:

LOC124903963 (HGNC:):

LOC124903963 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 17-28348239-C-T is Benign according to our data. Variant chr17-28348239-C-T is described in ClinVar as [Benign]. Clinvar id is 731416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00113 (172/152304) while in subpopulation EAS AF= 0.0247 (128/5184). AF 95% confidence interval is 0.0212. There are 4 homozygotes in gnomad4. There are 88 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
POLDIP2	NM_015584.5 link	c.993-8G>A	splice_region_variant, intron_variant	Intron 10 of 10	ENST00000540200.6	NP_056399.1	Q9Y2S7
POLDIP2	NM_001290145.2 link	c.939-8G>A	splice_region_variant, intron_variant	Intron 10 of 10		NP_001277074.1	Q9Y2S7B4DEM9
LOC124903963	XR_007065687.1 link	n.10C>T	non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLDIP2	ENST00000540200.6 link	c.993-8G>A		splice_region_variant, intron_variant	Intron 10 of 10	1	NM_015584.5	ENSP00000475924.2		Q9Y2S7
POLDIP2	ENST00000618887.2 link	c.939-8G>A		splice_region_variant, intron_variant	Intron 10 of 10	2		ENSP00000477665.2		B4DEM9

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.0246

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00222

AC:

553

AN:

248716

Hom.:

AF XY:

0.00204

AC XY:

276

AN XY:

134980

show subpopulations

Gnomad AFR exome

AF:

0.000129

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00249

Gnomad EAS exome

AF:

0.0263

Gnomad SAS exome

AF:

0.000916

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00169

AC:

2441

AN:

1448456

Hom.:

Cov.:

AF XY:

0.00167

AC XY:

1204

AN XY:

721618

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.0000671

Gnomad4 ASJ exome

AF:

0.00269

Gnomad4 EAS exome

AF:

0.0499

Gnomad4 SAS exome

AF:

0.00129

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000120

Gnomad4 OTH exome

AF:

0.00230

GnomAD4 genome

AF:

0.00113

AC:

172

AN:

152304

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.0247

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000473

Hom.:

Bravo

AF:

0.00126

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

1.7

DANN

Benign

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000036

dbscSNV1_RF

Benign

0.0020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over