17-28357342-G-C

Variant names:

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

Variant summary

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

The NM_015584.5(POLDIP2):​c.107C>G​(p.Ala36Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000703 in 1,422,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/14 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A36V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: POLDIP2 NM_015584.5 missense
• Clinical Significance: Not reported in ClinVar
• 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: 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 (MetaRNN=0.21484286).

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>G	p.Ala36Gly	missense	Exon 1 of 11	NP_056399.1	Q9Y2S7
	POLDIP2	NM_001290145.2		c.107C>G	p.Ala36Gly	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>G	p.Ala36Gly	missense	Exon 1 of 11	ENSP00000475924.2	Q9Y2S7
	POLDIP2	ENST00000902298.1		c.107C>G	p.Ala36Gly	missense	Exon 1 of 11	ENSP00000572357.1
	POLDIP2	ENST00000902300.1		c.107C>G	p.Ala36Gly	missense	Exon 1 of 11	ENSP00000572359.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000669 AC: 1 AN: 149492 AF XY: 0.0000116

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.03e-7 AC: 1 AN: 1422670 Hom.: 0 Cov.: 32 AF XY: 0.00000141 AC XY: 1 AN XY: 707498

⚠️ 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: 30610

American (AMR) AF: 0.00 AC: 0 AN: 43124

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25320

East Asian (EAS) AF: 0.00 AC: 0 AN: 37096

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36186

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4574

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1102934

Other (OTH) AF: 0.00 AC: 0 AN: 59154

⚠️ 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.: 33

ExAC AF: 0.00000906 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	16
DANN	Benign	0.55
DEOGEN2	Benign	0.026	T
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.69	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.21	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.52
PrimateAI	Uncertain	0.69	T
Sift4G	Benign	0.090	T
Polyphen		0.016	B
Vest4		0.29
MVP		0.80
MPC		0.54
GERP RS		1.6
PromoterAI		0.11	Neutral
Varity_R		0.030
gMVP		0.20

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;