rs2228665

Positions:

• chr19-50399402-C-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002691.4(POLD1):​c.234C>G​(p.Arg78=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00604 in 1,614,070 control chromosomes in the GnomAD database, including 521 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (276 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (245 hom.)
• Consequence: POLD1 NM_002691.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.657

Genes affected

POLD1 (HGNC:9175): (DNA polymerase delta 1, catalytic subunit) This gene encodes the 125-kDa catalytic subunit of DNA polymerase delta. DNA polymerase delta possesses both polymerase and 3' to 5' exonuclease activity and plays a critical role in DNA replication and repair. Alternatively spliced transcript variants have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 6. [provided by RefSeq, Mar 2012]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 19-50399402-C-G is Benign according to our data. Variant chr19-50399402-C-G is described in ClinVar as [Benign]. Clinvar id is 380633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50399402-C-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.657 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POLD1	NM_002691.4	c.234C>G	p.Arg78=	synonymous_variant	3/27	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.234C>G	p.Arg78=	synonymous_variant	3/27	1	NM_002691.4	ENSP00000406046	P1

Frequencies

GnomAD3 genomes AF: 0.0328 AC: 4986 AN: 152212 Hom.: 274 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.0244

GnomAD3 exomes AF: 0.00871 AC: 2190 AN: 251380 Hom.: 115 AF XY: 0.00612 AC XY: 831 AN XY: 135880

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.00717

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000255

Gnomad OTH exome AF: 0.00440

GnomAD4 exome AF: 0.00325 AC: 4748 AN: 1461740 Hom.: 245 Cov.: 31 AF XY: 0.00275 AC XY: 2003 AN XY: 727188

Gnomad4 AFR exome AF: 0.113

Gnomad4 AMR exome AF: 0.00800

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000105

Gnomad4 OTH exome AF: 0.00732

GnomAD4 genome AF: 0.0328 AC: 5003 AN: 152330 Hom.: 276 Cov.: 32 AF XY: 0.0318 AC XY: 2367 AN XY: 74492

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.0241

Alfa AF: 0.00950 Hom.: 14

Bravo AF: 0.0380

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 04, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Dec 06, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Aug 15, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 17, 2016	Variant summary: The POLD1 c.234C>G (p.Arg78Arg) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 1258/120890 control chromosomes (73 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.1125917 (1166/10356). This frequency is about 7926 times the estimated maximal expected allele frequency of a pathogenic POLD1 variant (0.0000142), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Colorectal cancer, susceptibility to, 10 Benign:2

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Oct 25, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 20, 2015	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Carcinoma of colon Benign:1

Benign, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The POLD1 p.Arg78= variant was identified in dbSNP (ID: rs2228665) “With Benign allele”, ClinVar (classified benign by GeneDx, Invitae, Ambry Genetics and Quest Diagnostics Nichols Institute San Juan Capistrano), and in control databases in 3050 (173 homozygous) of 277140 chromosomes at a frequency of 0.01 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 2735 (171 homozygous) of 24022 chromosomes (freq: 0.11), Other in 27 of 6466 chromosomes (freq: 0.004), Latino in 253 (2 homozygous) of 34418 chromosomes (freq: 0.007), European Non-Finnish in 32 of 126664 chromosomes (freq: 0.0003), Ashkenazi Jewish in 1 of 10150 chromosomes (freq: 0.0001), and South Asian in 2 of 30782 chromosomes (freq: 0.00007), while not observed in the East Asian and European Finnish populations. The p.Arg78= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.6
DANN	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs2228665; hg19: chr19-50902659;