rs487989

chr11-65297219-G-Achr11-65297219-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002689.4(POLA2):c.1747G>A(p.Gly583Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,613,582 control chromosomes in the GnomAD database, including 18,076 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (1689 hom., cov: 32)
  • Exomes 𝑓: 0.15 (16387 hom.)
• Consequence: POLA2 NM_002689.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.239

Genes affected

POLA2 (HGNC:30073): (DNA polymerase alpha 2, accessory subunit) Predicted to enable DNA binding activity. Involved in DNA replication, synthesis of RNA primer. Located in cytosol and nucleoplasm. Part of alpha DNA polymerase:primase complex. [provided by Alliance of Genome Resources, Apr 2022]

LOC105369344 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.2425604E-4).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.196 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POLA2	NM_002689.4	c.1747G>A	p.Gly583Arg	missense_variant	18/18	ENST00000265465.8
LOC105369344	XR_007062727.1	n.1115-1595C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POLA2	ENST00000265465.8	c.1747G>A	p.Gly583Arg	missense_variant	18/18	1	NM_002689.4	P1

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21916 AN: 152082 Hom.: 1689 Cov.: 32

Gnomad AFR AF: 0.170

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.159

Gnomad ASJ AF: 0.196

Gnomad EAS AF: 0.0843

Gnomad SAS AF: 0.207

Gnomad FIN AF: 0.0755

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.134

Gnomad OTH AF: 0.160

GnomAD3 exomes AF: 0.143 AC: 35797 AN: 250644 Hom.: 2754 AF XY: 0.145 AC XY: 19631 AN XY: 135460

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.0854

Gnomad SAS exome AF: 0.206

Gnomad FIN exome AF: 0.0824

Gnomad NFE exome AF: 0.134

Gnomad OTH exome AF: 0.136

GnomAD4 exome AF: 0.147 AC: 214672 AN: 1461382 Hom.: 16387 Cov.: 32 AF XY: 0.148 AC XY: 107925 AN XY: 726988

Gnomad4 AFR exome AF: 0.169

Gnomad4 AMR exome AF: 0.156

Gnomad4 ASJ exome AF: 0.194

Gnomad4 EAS exome AF: 0.0735

Gnomad4 SAS exome AF: 0.202

Gnomad4 FIN exome AF: 0.0851

Gnomad4 NFE exome AF: 0.146

Gnomad4 OTH exome AF: 0.155

GnomAD4 genome AF: 0.144 AC: 21922 AN: 152200 Hom.: 1689 Cov.: 32 AF XY: 0.143 AC XY: 10634 AN XY: 74426

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.159

Gnomad4 ASJ AF: 0.196

Gnomad4 EAS AF: 0.0847

Gnomad4 SAS AF: 0.206

Gnomad4 FIN AF: 0.0755

Gnomad4 NFE AF: 0.134

Gnomad4 OTH AF: 0.158

Alfa AF: 0.137 Hom.: 3643

Bravo AF: 0.150

TwinsUK AF: 0.149 AC: 552

ALSPAC AF: 0.147 AC: 567

ESP6500AA AF: 0.175 AC: 769

ESP6500EA AF: 0.142 AC: 1218

ExAC AF: 0.143 AC: 17328

Asia WGS AF: 0.130 AC: 452 AN: 3478

EpiCase AF: 0.140

EpiControl AF: 0.141

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	6.2
Dann	Benign	0.88
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.00072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.089
Sift	Benign	0.33	T
Sift4G	Benign	0.096	T
Polyphen		0.47	P
Vest4		0.013
MutPred		0.15		Gain of MoRF binding (P = 0.0328);
MPC		0.21
ClinPred		0.0053	T
GERP RS		-0.78
Varity_R		0.053
gMVP		0.63

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: rs487989; hg19: chr11-65064690; COSMIC: COSV55483426; COSMIC: COSV55483426;