rs487989

Variant names:

• chr11-65297219-G-A
• rs487989
• NM_002689.4:c.1747G>A

Your query was ambiguous. Multiple possible variants found:

• chr11-65297219-G-A
• chr11-65297219-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2 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. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 50 publications found

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]

POLA2 Gene-Disease associations (from GenCC):

• telomere syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000285816 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -11 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 1.0585 (below the threshold of 3.09). Trascript score misZ: 1.5804 (below the threshold of 3.09). GenCC associations: The gene is linked to telomere syndrome.
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002689.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLA2	NM_002689.4	MANE Select	c.1747G>A	p.Gly583Arg	missense	Exon 18 of 18	NP_002680.2
	POLA2	NM_001437761.1		c.*114G>A		3_prime_UTR	Exon 18 of 18	NP_001424690.1	A0A9L9PY44
	POLA2	NM_001438747.1		c.1647+1229G>A		intron	N/A	NP_001425676.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POLA2	ENST00000265465.8	TSL:1 MANE Select	c.1747G>A	p.Gly583Arg	missense	Exon 18 of 18	ENSP00000265465.3	Q14181-1
	ENSG00000285816	ENST00000649896.1		n.1647+1229G>A		intron	N/A	ENSP00000498025.1	A0A3B3ITS5
	POLA2	ENST00000875243.1		c.1597G>A	p.Gly533Arg	missense	Exon 16 of 16	ENSP00000545302.1

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

GnomAD2 exomes AF: 0.143 AC: 35797 AN: 250644 AF XY: 0.145

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 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

African (AFR) AF: 0.169 AC: 5667 AN: 33464

American (AMR) AF: 0.156 AC: 6953 AN: 44650

Ashkenazi Jewish (ASJ) AF: 0.194 AC: 5054 AN: 26110

East Asian (EAS) AF: 0.0735 AC: 2916 AN: 39700

South Asian (SAS) AF: 0.202 AC: 17444 AN: 86208

European-Finnish (FIN) AF: 0.0851 AC: 4539 AN: 53350

Middle Eastern (MID) AF: 0.145 AC: 836 AN: 5768

European-Non Finnish (NFE) AF: 0.146 AC: 161894 AN: 1111760

Other (OTH) AF: 0.155 AC: 9369 AN: 60372

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

African (AFR) AF: 0.169 AC: 7034 AN: 41520

American (AMR) AF: 0.159 AC: 2428 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.196 AC: 679 AN: 3468

East Asian (EAS) AF: 0.0847 AC: 438 AN: 5174

South Asian (SAS) AF: 0.206 AC: 996 AN: 4826

European-Finnish (FIN) AF: 0.0755 AC: 801 AN: 10610

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.134 AC: 9112 AN: 68004

Other (OTH) AF: 0.158 AC: 334 AN: 2114

Alfa AF: 0.138 Hom.: 7039

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 v4.9

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
PhyloP100		0.24
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
Mutation Taster		=94/6	polymorphism (auto)

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