1-27894054-T-C

Position:

• chr1-27894054-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002946.5(RPA2):​c.686A>G​(p.Asp229Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D229E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RPA2 NM_002946.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.66

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RPA2	NM_002946.5	c.686A>G	p.Asp229Gly	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.686A>G	p.Asp229Gly	missense_variant	8/9	1	NM_002946.5	ENSP00000363021.3
RPA2	ENST00000313433.11	c.950A>G	p.Asp317Gly	missense_variant	7/8	1		ENSP00000363015.3
RPA2	ENST00000373909.7	c.710A>G	p.Asp237Gly	missense_variant	8/9	3		ENSP00000363017.3
RPA2	ENST00000419958.5	c.242A>G	p.Asp81Gly	missense_variant	3/5	3		ENSP00000413541.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Mar 22, 2023

The c.686A>G (p.D229G) alteration is located in exon 8 (coding exon 8) of the RPA2 gene. This alteration results from a A to G substitution at nucleotide position 686, causing the aspartic acid (D) at amino acid position 229 to be replaced by a glycine (G). 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	Uncertain	0.53
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;T;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D;D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Uncertain	0.48	T;T;T;T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.9	M;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.5	D;D;D;D
REVEL	Benign	0.19
Sift	Uncertain	0.016	D;D;D;D
Sift4G	Benign	0.064	T;D;T;D
Polyphen		0.90	P;.;P;.
Vest4		0.53
MutPred		0.52		Loss of ubiquitination at K231 (P = 0.0578);.;.;.;
MVP		0.51
MPC		0.87
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.93
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: chr1-28220565;