1-27894088-C-A

Position:

• chr1-27894088-C-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002946.5(RPA2):​c.652G>T​(p.Ala218Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: RPA2 NM_002946.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0940209).
• BS2: High AC in GnomAdExome4 at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPA2	NM_002946.5	c.652G>T	p.Ala218Ser	missense_variant	8/9	ENST00000373912.8	NP_002937.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RPA2	ENST00000373912.8	c.652G>T	p.Ala218Ser	missense_variant	8/9	1	NM_002946.5	ENSP00000363021.3
RPA2	ENST00000313433.11	c.916G>T	p.Ala306Ser	missense_variant	7/8	1		ENSP00000363015.3
RPA2	ENST00000373909.7	c.676G>T	p.Ala226Ser	missense_variant	8/9	3		ENSP00000363017.3
RPA2	ENST00000419958.5	c.208G>T	p.Ala70Ser	missense_variant	3/5	3		ENSP00000413541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000239 AC: 6 AN: 251356 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135874

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461660 Hom.: 0 Cov.: 30 AF XY: 0.0000138 AC XY: 10 AN XY: 727128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000576 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 05, 2024

The c.652G>T (p.A218S) alteration is located in exon 8 (coding exon 8) of the RPA2 gene. This alteration results from a G to T substitution at nucleotide position 652, causing the alanine (A) at amino acid position 218 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.033	T;T;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	0.018
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.64	T;T;T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.094	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.42	N;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Benign	0.63	N;N;N;N
REVEL	Benign	0.018
Sift	Benign	0.71	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0090	B;.;B;.
Vest4		0.10
MutPred		0.44		Gain of disorder (P = 0.074);.;.;.;
MVP		0.32
MPC		0.25
ClinPred		0.076	T
GERP RS		5.3
Varity_R		0.25
gMVP		0.17

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: rs751138848; hg19: chr1-28220599;