rs1064792946

Variant names:

• chr19-50402262-T-TGCCGCGCCTCGTGGCCCC
• rs1064792946
• NM_002691.4:c.649_666dupCCGCGCCTCGTGGCCCCG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_002691.4(POLD1):​c.649_666dupCCGCGCCTCGTGGCCCCG​(p.Pro217_Pro222dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,450,700 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: POLD1 NM_002691.4 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.35
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_002691.4.

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.649_666dupCCGCGCCTCGTGGCCCCG	p.Pro217_Pro222dup	conservative_inframe_insertion	Exon 6 of 27	NP_002682.2
	POLD1	NM_001308632.1		c.649_666dupCCGCGCCTCGTGGCCCCG	p.Pro217_Pro222dup	conservative_inframe_insertion	Exon 5 of 26	NP_001295561.1
	POLD1	NM_001256849.1		c.649_666dupCCGCGCCTCGTGGCCCCG	p.Pro217_Pro222dup	conservative_inframe_insertion	Exon 6 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.649_666dupCCGCGCCTCGTGGCCCCG	p.Pro217_Pro222dup	conservative_inframe_insertion	Exon 6 of 27	ENSP00000406046.1
	POLD1	ENST00000595904.6	TSL:1	c.649_666dupCCGCGCCTCGTGGCCCCG	p.Pro217_Pro222dup	conservative_inframe_insertion	Exon 6 of 27	ENSP00000472445.1
	POLD1	ENST00000599857.7	TSL:1	c.649_666dupCCGCGCCTCGTGGCCCCG	p.Pro217_Pro222dup	conservative_inframe_insertion	Exon 6 of 27	ENSP00000473052.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450700 Hom.: 0 Cov.: 34 AF XY: 0.00000139 AC XY: 1 AN XY: 720518

African (AFR) AF: 0.00 AC: 0 AN: 33214

American (AMR) AF: 0.00 AC: 0 AN: 43636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25364

East Asian (EAS) AF: 0.00 AC: 0 AN: 39544

South Asian (SAS) AF: 0.00 AC: 0 AN: 84652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105786

Other (OTH) AF: 0.00 AC: 0 AN: 59850

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Colorectal cancer, susceptibility to, 10 (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1064792946; hg19: chr19-50905519;