19-50402057-G-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7

The NM_002691.4(POLD1):c.522G>C(p.Arg174Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,948 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R174R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

POLD1
NM_002691.4 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 3.58

Publications

0 publications found

Variant links:

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

POLD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 19-50402057-G-C is Benign according to our data. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584. Variant chr19-50402057-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 700584.

BP7

Synonymous conserved (PhyloP=3.58 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4 link	c.522G>C	p.Arg174Arg	synonymous_variant	Exon 5 of 27	ENST00000440232.7	NP_002682.2	P28340A0A024R4F4Q59FA0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7 link	c.522G>C	p.Arg174Arg	synonymous_variant	Exon 5 of 27	1	NM_002691.4	ENSP00000406046.1		P28340

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000399

AC:

AN:

250922

AF XY:

0.00

show subpopulations

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:

0.00000342

AC:

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727212

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26122

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000360

AC:

AN:

1111970

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68016

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 20, 2019

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at a significant frequency in large population cohorts (Lek et al., 2016) -

Colorectal cancer, susceptibility to, 10

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Oct 17, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

8.0

(source)

DANN

Benign

0.62

PhyloP100

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over