17-28357342-G-A

Variant names:

• chr17-28357342-G-A
• rs11555978
• NM_015584.5:c.107C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_015584.5(POLDIP2):​c.107C>T​(p.Ala36Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0249 in 1,574,966 control chromosomes in the GnomAD database, including 613 homozygotes. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (31 hom., cov: 33)
  • Exomes 𝑓: 0.026 (582 hom.)
• Consequence: POLDIP2 NM_015584.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.518
• Publications: 7 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025236309).
• BP6: Variant 17-28357342-G-A is Benign according to our data. Variant chr17-28357342-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1205722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2528/152354) while in subpopulation NFE AF = 0.027 (1838/68024). AF 95% confidence interval is 0.026. There are 31 homozygotes in GnomAd4. There are 1134 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 31 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015584.5. 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
	POLDIP2	NM_015584.5	MANE Select	c.107C>T	p.Ala36Val	missense	Exon 1 of 11	NP_056399.1	Q9Y2S7
	POLDIP2	NM_001290145.2		c.107C>T	p.Ala36Val	missense	Exon 1 of 11	NP_001277074.1	B4DEM9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLDIP2	ENST00000540200.6	TSL:1 MANE Select	c.107C>T	p.Ala36Val	missense	Exon 1 of 11	ENSP00000475924.2	Q9Y2S7
	POLDIP2	ENST00000902298.1		c.107C>T	p.Ala36Val	missense	Exon 1 of 11	ENSP00000572357.1
	POLDIP2	ENST00000902300.1		c.107C>T	p.Ala36Val	missense	Exon 1 of 11	ENSP00000572359.1

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2528 AN: 152236 Hom.: 31 Cov.: 33

Gnomad AFR AF: 0.00461

Gnomad AMI AF: 0.0484

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00351

Gnomad FIN AF: 0.0120

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0234

GnomAD2 exomes AF: 0.0215 AC: 3218 AN: 149492 AF XY: 0.0216

Gnomad AFR exome AF: 0.00621

Gnomad AMR exome AF: 0.0130

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.000117

Gnomad FIN exome AF: 0.0158

Gnomad NFE exome AF: 0.0346

Gnomad OTH exome AF: 0.0266

GnomAD4 exome AF: 0.0258 AC: 36651 AN: 1422612 Hom.: 582 Cov.: 32 AF XY: 0.0253 AC XY: 17875 AN XY: 707464

African (AFR) AF: 0.00412 AC: 126 AN: 30610

American (AMR) AF: 0.0119 AC: 515 AN: 43120

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 418 AN: 25320

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 37096

South Asian (SAS) AF: 0.00543 AC: 454 AN: 83672

European-Finnish (FIN) AF: 0.0140 AC: 506 AN: 36186

Middle Eastern (MID) AF: 0.0208 AC: 95 AN: 4574

European-Non Finnish (NFE) AF: 0.0301 AC: 33249 AN: 1102884

Other (OTH) AF: 0.0218 AC: 1287 AN: 59150

GnomAD4 genome AF: 0.0166 AC: 2528 AN: 152354 Hom.: 31 Cov.: 33 AF XY: 0.0152 AC XY: 1134 AN XY: 74498

African (AFR) AF: 0.00459 AC: 191 AN: 41590

American (AMR) AF: 0.0128 AC: 196 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00352 AC: 17 AN: 4834

European-Finnish (FIN) AF: 0.0120 AC: 128 AN: 10630

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0270 AC: 1838 AN: 68024

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0210 Hom.: 13

Bravo AF: 0.0172

TwinsUK AF: 0.0332 AC: 123

ALSPAC AF: 0.0324 AC: 125

ESP6500AA AF: 0.00350 AC: 11

ESP6500EA AF: 0.0215 AC: 152

ExAC AF: 0.0164 AC: 1810

Asia WGS AF: 0.00202 AC: 7 AN: 3476

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	16
DANN	Benign	0.82
DEOGEN2	Benign	0.014	T
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0025	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.52
PrimateAI	Uncertain	0.70	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.23
MPC		0.52
GERP RS		1.6
PromoterAI		0.022	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.023
gMVP		0.22
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs11555978; hg19: chr17-26684368;