rs17257252

Variant names:

• chr1-27893973-C-A
• rs17257252
• NM_002946.5:c.728+39G>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 24 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
RPA2	NM_002946.5	c.728+39G>T		intron_variant	Intron 8 of 8	ENST00000373912.8	NP_002937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPA2	ENST00000373912.8	c.728+39G>T		intron_variant	Intron 8 of 8	1	NM_002946.5	ENSP00000363021.3
RPA2	ENST00000313433.11	c.992+39G>T		intron_variant	Intron 7 of 7	1		ENSP00000363015.3
RPA2	ENST00000373909.7	c.752+39G>T		intron_variant	Intron 8 of 8	3		ENSP00000363017.3
RPA2	ENST00000419958.5	c.284+39G>T		intron_variant	Intron 3 of 4	3		ENSP00000413541.1

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

GnomAD2 exomes AF: 0.183 AC: 45091 AN: 246782 AF XY: 0.189

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 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

African (AFR) AF: 0.0349 AC: 1119 AN: 32044

American (AMR) AF: 0.0997 AC: 4399 AN: 44108

Ashkenazi Jewish (ASJ) AF: 0.223 AC: 5678 AN: 25484

East Asian (EAS) AF: 0.0813 AC: 3194 AN: 39288

South Asian (SAS) AF: 0.141 AC: 11903 AN: 84276

European-Finnish (FIN) AF: 0.262 AC: 13916 AN: 53134

Middle Eastern (MID) AF: 0.237 AC: 1334 AN: 5638

European-Non Finnish (NFE) AF: 0.233 AC: 244738 AN: 1048944

Other (OTH) AF: 0.201 AC: 11664 AN: 57944

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

African (AFR) AF: 0.0396 AC: 1647 AN: 41542

American (AMR) AF: 0.124 AC: 1899 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.222 AC: 770 AN: 3466

East Asian (EAS) AF: 0.103 AC: 533 AN: 5186

South Asian (SAS) AF: 0.138 AC: 668 AN: 4826

European-Finnish (FIN) AF: 0.257 AC: 2713 AN: 10560

Middle Eastern (MID) AF: 0.224 AC: 66 AN: 294

European-Non Finnish (NFE) AF: 0.234 AC: 15929 AN: 67972

Other (OTH) AF: 0.179 AC: 378 AN: 2114

Alfa AF: 0.207 Hom.: 6318

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
PhyloP100		-1.5
Mutation Taster		=100/0	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: rs17257252; hg19: chr1-28220484; COSMIC: COSV57878809; COSMIC: COSV57878809;