Genetic Variant POLD2:p.Gly466Ala (chr7-44114798-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006230.4(POLD2):c.1397G>C(p.Gly466Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G466E) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Consequence

POLD2
NM_006230.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.50

Publications

1 publications found

Variant links:

Genes affected

POLD2 (HGNC:9176): (DNA polymerase delta 2, accessory subunit) This gene encodes the 50-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. The encoded protein is required for the stimulation of DNA polymerase delta activity by the processivity cofactor proliferating cell nuclear antigen (PCNA). Expression of this gene may be a marker for ovarian carcinomas. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and a pseudogene of this gene is located on the long arm of chromosome 5. [provided by RefSeq, Mar 2012]

POLD2 links:

AEBP1 (HGNC:303): (AE binding protein 1) This gene encodes a member of carboxypeptidase A protein family. The encoded protein may function as a transcriptional repressor and play a role in adipogenesis and smooth muscle cell differentiation. Studies in mice suggest that this gene functions in wound healing and abdominal wall development. Overexpression of this gene is associated with glioblastoma. [provided by RefSeq, May 2013]

AEBP1 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome, classic-like, 2
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp

AEBP1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08727074).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006230.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLD2	NM_006230.4	MANE Select	c.1397G>C	p.Gly466Ala	missense	Exon 11 of 11	NP_006221.3	P49005
POLD2	NM_001127218.3		c.1397G>C	p.Gly466Ala	missense	Exon 11 of 11	NP_001120690.1	P49005
POLD2	NM_001256879.2		c.1397G>C	p.Gly466Ala	missense	Exon 12 of 12	NP_001243808.1	P49005

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
POLD2	ENST00000610533.6	TSL:1 MANE Select	c.1397G>C	p.Gly466Ala	missense	Exon 11 of 11	ENSP00000480186.2	P49005
POLD2	ENST00000452185.5	TSL:1	c.1397G>C	p.Gly466Ala	missense	Exon 11 of 11	ENSP00000395231.1	P49005
POLD2	ENST00000881309.1		c.1424G>C	p.Gly475Ala	missense	Exon 11 of 11	ENSP00000551368.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Benign

0.79

DEOGEN2

Benign

0.0066

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.36

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.70

M_CAP

Benign

0.0065

MetaRNN

Benign

0.087

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.060

PhyloP100

2.5

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.18

REVEL

Benign

0.023

Sift

Benign

0.14

Sift4G

Uncertain

0.051

Polyphen

0.016

Vest4

0.23

MutPred

0.27

Gain of catalytic residue at G466 (P = 0.117)

MVP

0.23

MPC

0.26

ClinPred

0.20

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.084

gMVP

0.57

Mutation Taster

=59/41

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over