rs6700473

Variant names:

• chr1-27910171-G-A
• rs6700473
• NM_002946.5:c.118-2889C>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.118-2889C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.332 in 151,940 control chromosomes in the GnomAD database, including 8,857 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 0.33 (8857 hom., cov: 32)
• Consequence: RPA2 NM_002946.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.95
• Publications: 11 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.501 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002946.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA2	NM_002946.5	MANE Select	c.118-2889C>T		intron	N/A	NP_002937.1
	RPA2	NM_001297558.1		c.142-2889C>T		intron	N/A	NP_001284487.1
	RPA2	NM_001355129.2		c.130-2889C>T		intron	N/A	NP_001342058.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RPA2	ENST00000373912.8	TSL:1 MANE Select	c.118-2889C>T		intron	N/A	ENSP00000363021.3
	RPA2	ENST00000313433.11	TSL:1	c.382-2889C>T		intron	N/A	ENSP00000363015.3
	RPA2	ENST00000373909.7	TSL:3	c.142-2889C>T		intron	N/A	ENSP00000363017.3

Frequencies

GnomAD3 genomes AF: 0.332 AC: 50350 AN: 151820 Hom.: 8851 Cov.: 32

Gnomad AFR AF: 0.219

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.340

Gnomad ASJ AF: 0.366

Gnomad EAS AF: 0.517

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.421

Gnomad NFE AF: 0.372

Gnomad OTH AF: 0.352

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.332 AC: 50374 AN: 151940 Hom.: 8857 Cov.: 32 AF XY: 0.330 AC XY: 24524 AN XY: 74266

African (AFR) AF: 0.220 AC: 9111 AN: 41454

American (AMR) AF: 0.340 AC: 5186 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.366 AC: 1270 AN: 3468

East Asian (EAS) AF: 0.518 AC: 2672 AN: 5160

South Asian (SAS) AF: 0.323 AC: 1557 AN: 4816

European-Finnish (FIN) AF: 0.375 AC: 3951 AN: 10524

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.372 AC: 25265 AN: 67954

Other (OTH) AF: 0.348 AC: 735 AN: 2112

Alfa AF: 0.353 Hom.: 2703

Bravo AF: 0.331

Asia WGS AF: 0.337 AC: 1168 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.052
DANN	Benign	0.46
PhyloP100		-1.9
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: rs6700473; hg19: chr1-28236682;