19-50399402-C-G

Variant names:

• chr19-50399402-C-G
• rs2228665
• NM_002691.4:c.234C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002691.4(POLD1):​c.234C>G​(p.Arg78Arg) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R78R) has been classified as Likely 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:14
• Conservation: PhyloP100: 0.657
• Publications: 5 publications found

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]

POLD1 Gene-Disease associations (from GenCC):

• POLD1-related polyposis and colorectal cancer syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• colorectal cancer, susceptibility to, 10

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• mandibular hypoplasia-deafness-progeroid syndrome

  Inheritance: AD, AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia, Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
• Polymerase proofreading-related adenomatous polyposis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• immunodeficiency 120

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics
• non-severe combined immunodeficiency due to polymerase delta deficiency

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 380633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002691.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	NM_002691.4	MANE Select	c.234C>G	p.Arg78Arg	synonymous	Exon 3 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.234C>G	p.Arg78Arg	synonymous	Exon 2 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.234C>G	p.Arg78Arg	synonymous	Exon 3 of 27	NP_001243778.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLD1	ENST00000440232.7	TSL:1 MANE Select	c.234C>G	p.Arg78Arg	synonymous	Exon 3 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.234C>G	p.Arg78Arg	synonymous	Exon 3 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.234C>G	p.Arg78Arg	synonymous	Exon 3 of 27	ENSP00000473052.1

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

GnomAD2 exomes AF: 0.00871 AC: 2190 AN: 251380 AF XY: 0.00612

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 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

African (AFR) AF: 0.113 AC: 3791 AN: 33464

American (AMR) AF: 0.00800 AC: 358 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000197 AC: 17 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5768

European-Non Finnish (NFE) AF: 0.000105 AC: 117 AN: 1111898

Other (OTH) AF: 0.00732 AC: 442 AN: 60380

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

African (AFR) AF: 0.113 AC: 4710 AN: 41558

American (AMR) AF: 0.0142 AC: 217 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000323 AC: 22 AN: 68034

Other (OTH) AF: 0.0241 AC: 51 AN: 2114

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:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Aug 04, 2016

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 06, 2016

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 13, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Hereditary cancer-predisposing syndrome Benign:3

May 20, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Oct 25, 2017

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 20, 2025

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The synonymous variant NM_001308632.1(POLD1):c.234C>G (p.Arg78=) has been reported to ClinVar as Benign with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 380633 as of 2025-01-02). The variant is observed in one or more well-documented healthy adults.The p.Arg78= variant is observed in 177/5,008 (3.5343%) alleles from individuals of 1kG All background in 1kG, indicating it is a common benign variant. The p.Arg78= variant is not predicted to disrupt an existing splice site. The p.Arg78= variant results in a substitution of a base that is not predicted conserved by GERP++ and PhyloP. For these reasons, this variant has been classified as Benign.

not provided Benign:2

May 17, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Colorectal cancer, susceptibility to, 10 Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Carcinoma of colon Benign:1

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.6
DANN	Benign	0.74
PhyloP100		0.66
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs2228665; hg19: chr19-50902659;