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GeneBe

1-27914065-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002946.5(RPA2):c.115T>C(p.Ser39Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

RPA2
NM_002946.5 missense, splice_region

Scores

2
17
Splicing: ADA: 0.001371
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.67
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.16382802).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
RPA2NM_002946.5 linkuse as main transcriptc.115T>C p.Ser39Pro missense_variant, splice_region_variant 2/9 ENST00000373912.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
RPA2ENST00000373912.8 linkuse as main transcriptc.115T>C p.Ser39Pro missense_variant, splice_region_variant 2/91 NM_002946.5 P1P15927-1
RPA2ENST00000313433.11 linkuse as main transcriptc.379T>C p.Ser127Pro missense_variant, splice_region_variant 1/81 P15927-3
RPA2ENST00000373909.7 linkuse as main transcriptc.139T>C p.Ser47Pro missense_variant, splice_region_variant 2/93 P15927-2
RPA2ENST00000444045.1 linkuse as main transcriptc.127T>C p.Ser43Pro missense_variant, splice_region_variant 2/65

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 18, 2023The c.115T>C (p.S39P) alteration is located in exon 2 (coding exon 2) of the RPA2 gene. This alteration results from a T to C substitution at nucleotide position 115, causing the serine (S) at amino acid position 39 to be replaced by a proline (P). 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
0.15
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.40
Cadd
Benign
21
Dann
Uncertain
0.99
DEOGEN2
Benign
0.10
T;.;.;T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.14
FATHMM_MKL
Benign
0.65
D
LIST_S2
Benign
0.63
T;T;T;T
M_CAP
Benign
0.036
D
MetaRNN
Benign
0.16
T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.9
L;.;.;.
MutationTaster
Benign
0.93
D;D;D
PrimateAI
Uncertain
0.52
T
PROVEAN
Benign
-2.0
N;N;N;N
REVEL
Benign
0.042
Sift
Benign
0.26
T;T;T;T
Sift4G
Benign
0.33
T;T;T;T
Polyphen
0.026
B;B;.;.
Vest4
0.13
MutPred
0.28
Loss of phosphorylation at S39 (P = 0.0382);.;.;.;
MVP
0.40
MPC
0.65
ClinPred
0.81
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.34
gMVP
0.54

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0014
dbscSNV1_RF
Benign
0.056
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-28240576; API