chr19-50407184-C-T

Variant names:

• chr19-50407184-C-T
• rs372652150
• NM_002691.4:c.1686+10C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_002691.4(POLD1):​c.1686+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000716 in 1,592,908 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000071 (0 hom.)
• Consequence: POLD1 NM_002691.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -3.19
• Publications: 0 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 19-50407184-C-T is Benign according to our data. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-50407184-C-T is described in CliVar as Likely_benign. Clinvar id is 220860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD1	NM_002691.4	c.1686+10C>T		intron_variant	Intron 13 of 26	ENST00000440232.7	NP_002682.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD1	ENST00000440232.7	c.1686+10C>T		intron_variant	Intron 13 of 26	1	NM_002691.4	ENSP00000406046.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152158 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000332 AC: 8 AN: 241148 AF XY: 0.0000306

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000555

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000715 AC: 103 AN: 1440750 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 48 AN XY: 713104

African (AFR) AF: 0.0000302 AC: 1 AN: 33074

American (AMR) AF: 0.00 AC: 0 AN: 43818

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25440

East Asian (EAS) AF: 0.0000766 AC: 3 AN: 39168

South Asian (SAS) AF: 0.0000352 AC: 3 AN: 85268

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.0000830 AC: 91 AN: 1096948

Other (OTH) AF: 0.0000843 AC: 5 AN: 59322

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152158 Hom.: 0 Cov.: 30 AF XY: 0.0000673 AC XY: 5 AN XY: 74342

African (AFR) AF: 0.000121 AC: 5 AN: 41436

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.000102 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

May 30, 2017

GeneDx

Significance: Likely 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. -

Sep 12, 2019

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 05, 2023

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: POLD1 c.1686+10C>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.3e-05 in 241148 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1686+10C>T in individuals affected with Colorectal Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Colorectal cancer, susceptibility to, 10 Benign:2

Feb 07, 2025

Myriad Genetics, Inc.

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign. This variant is intronic and is not expected to impact mRNA splicing. -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely 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: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The POLD1 c.1686+10C>T variant was not identified in the literature. The variant was identified dbSNP (rs372652150) as “with likely benign allele” and ClinVar (classified as likely benign by Invitae and GeneDx). The variant was identified in control databases in 11 of 267,230 chromosomes at a frequency of 0.00004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 2 of 23,800 chromosomes (freq: 0.00008), European in 7 of 123,466 chromosomes (freq: 0.00006), East Asian in 1 of 18,704 chromosomes (freq: 0.00005), and South Asian in 1 of 29,814 chromosomes (freq: 0.00003). The variant was not observed in the Other, Latino, Ashkenazi Jewish, or Finnish, populations. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.39
DANN	Benign	0.85
PhyloP100		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs372652150; hg19: chr19-50910441; COSMIC: COSV70954692; COSMIC: COSV70954692;