rs17257252

chr1-27893973-C-A

Variant summary

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

The NM_002946.5(RPA2):c.728+39G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,543,006 control chromosomes in the GnomAD database, including 36,448 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.16 (2611 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33837 hom.)
• Consequence: RPA2 NM_002946.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.49

Genes affected

RPA2 (HGNC:10290): (replication protein A2) This gene encodes a subunit of the heterotrimeric Replication Protein A (RPA) complex, which binds to single-stranded DNA (ssDNA), forming a nucleoprotein complex that plays an important role in DNA metabolism, being involved in DNA replication, repair, recombination, telomere maintenance, and co-ordinating the cellular response to DNA damage through activation of the ataxia telangiectasia and Rad3-related protein (ATR) kinase. The RPA complex protects single-stranded DNA from nucleases, prevents formation of secondary structures that would interfere with repair, and co-ordinates the recruitment and departure of different genome maintenance factors. The heterotrimeric complex has two different modes of ssDNA binding, a low-affinity and high-affinity mode, determined by which oligonucleotide/oligosaccharide-binding (OB) domains of the complex are utilized, and differing in the length of DNA bound. This subunit contains a single OB domain that participates in high-affinity DNA binding and also contains a winged helix domain at its carboxy terminus, which interacts with many genome maintenance protein. Post-translational modifications of the RPA complex also plays a role in co-ordinating different damage response pathways. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.231 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPA2	NM_002946.5	c.728+39G>T		intron_variant		ENST00000373912.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPA2	ENST00000373912.8	c.728+39G>T		intron_variant		1	NM_002946.5	P1
RPA2	ENST00000313433.11	c.992+39G>T		intron_variant		1
RPA2	ENST00000373909.7	c.752+39G>T		intron_variant		3
RPA2	ENST00000419958.5	c.284+39G>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.164 AC: 24948 AN: 152028 Hom.: 2612 Cov.: 32

Gnomad AFR AF: 0.0397

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.222

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.138

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.218

Gnomad NFE AF: 0.234

Gnomad OTH AF: 0.182

GnomAD3 exomes AF: 0.183 AC: 45091 AN: 246782 Hom.: 4661 AF XY: 0.189 AC XY: 25215 AN XY: 133384

Gnomad AFR exome AF: 0.0363

Gnomad AMR exome AF: 0.0947

Gnomad ASJ exome AF: 0.220

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.140

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.233

Gnomad OTH exome AF: 0.204

GnomAD4 exome AF: 0.214 AC: 297945 AN: 1390860 Hom.: 33837 Cov.: 21 AF XY: 0.214 AC XY: 148343 AN XY: 694668

Gnomad4 AFR exome AF: 0.0349

Gnomad4 AMR exome AF: 0.0997

Gnomad4 ASJ exome AF: 0.223

Gnomad4 EAS exome AF: 0.0813

Gnomad4 SAS exome AF: 0.141

Gnomad4 FIN exome AF: 0.262

Gnomad4 NFE exome AF: 0.233

Gnomad4 OTH exome AF: 0.201

GnomAD4 genome AF: 0.164 AC: 24943 AN: 152146 Hom.: 2611 Cov.: 32 AF XY: 0.162 AC XY: 12029 AN XY: 74368

Gnomad4 AFR AF: 0.0396

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.222

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.138

Gnomad4 FIN AF: 0.257

Gnomad4 NFE AF: 0.234

Gnomad4 OTH AF: 0.179

Alfa AF: 0.213 Hom.: 5316

Bravo AF: 0.153

Asia WGS AF: 0.0930 AC: 322 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.069
Dann	Benign	0.60

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: rs17257252; hg19: chr1-28220484; COSMIC: COSV57878809; COSMIC: COSV57878809;