rs774269295

Variant names:

• chr7-44114798-C-G
• rs774269295
• NM_006230.4:c.1397G>C

Your query was ambiguous. Multiple possible variants found:

• chr7-44114798-C-G
• chr7-44114798-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_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. 15/21 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.50

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08727074).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POLD2	NM_006230.4	c.1397G>C	p.Gly466Ala	missense_variant	Exon 11 of 11	ENST00000610533.6	NP_006221.3
AEBP1	NM_001129.5	c.*537C>G		downstream_gene_variant		ENST00000223357.8	NP_001120.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POLD2	ENST00000610533.6	c.1397G>C	p.Gly466Ala	missense_variant	Exon 11 of 11	1	NM_006230.4	ENSP00000480186.2
AEBP1	ENST00000223357.8	c.*537C>G		downstream_gene_variant		1	NM_001129.5	ENSP00000223357.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 24, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 501 of the POLD2 protein (p.Gly501Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with POLD2-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	16
DANN	Benign	0.79
DEOGEN2	Benign	0.0066	T;T;.;T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.36
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.70	T;.;T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.087	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.060	.;N;.;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.18	.;N;N;N
REVEL	Benign	0.023
Sift	Benign	0.14	.;T;T;T
Sift4G	Uncertain	0.051	T;T;T;T
Polyphen		0.016, 0.027	.;B;B;B
Vest4		0.23
MutPred		0.27		.;Gain of catalytic residue at G466 (P = 0.117);.;Gain of catalytic residue at G466 (P = 0.117);
MVP		0.23
MPC		0.26
ClinPred		0.20	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.084
gMVP		0.57

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

LitVar

Other links and lift over

dbSNP: rs774269295; hg19: chr7-44154397;