Genetic Variant RAD52:p.Glu288Asp (chr12-916345-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_134424.4(RAD52):c.864G>C(p.Glu288Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 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)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

RAD52
NM_134424.4 missense, splice_region

Scores

Splicing: ADA: 0.0002009

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0380

Publications

0 publications found

Variant links:

Genes affected

RAD52 (HGNC:9824): (RAD52 homolog, DNA repair protein) The protein encoded by this gene shares similarity with Saccharomyces cerevisiae Rad52, a protein important for DNA double-strand break repair and homologous recombination. This gene product was shown to bind single-stranded DNA ends, and mediate the DNA-DNA interaction necessary for the annealing of complementary DNA strands. It was also found to interact with DNA recombination protein RAD51, which suggested its role in RAD51 related DNA recombination and repair. A pseudogene of this gene is present on chromosome 2. Alternative splicing results in multiple transcript variants. Additional alternatively spliced transcript variants of this gene have been described, but their full-length nature is not known. [provided by RefSeq, Jul 2014]

RAD52 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.04624036).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_134424.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAD52	NM_134424.4	MANE Select	c.864G>C	p.Glu288Asp	missense splice_region	Exon 9 of 12	NP_602296.2	Q5DR82
RAD52	NM_001297419.1		c.864G>C	p.Glu288Asp	missense splice_region	Exon 9 of 12	NP_001284348.1	Q5DR82
RAD52	NM_001297421.2		c.633G>C	p.Glu211Asp	missense splice_region	Exon 7 of 10	NP_001284350.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RAD52	ENST00000358495.8	TSL:1 MANE Select	c.864G>C	p.Glu288Asp	missense splice_region	Exon 9 of 12	ENSP00000351284.3	P43351-1
RAD52	ENST00000430095.6	TSL:1	c.864G>C	p.Glu288Asp	missense splice_region	Exon 9 of 12	ENSP00000387901.2	P43351-1
RAD52	ENST00000461568.5	TSL:1	n.*702G>C		splice_region non_coding_transcript_exon	Exon 10 of 12	ENSP00000436008.1	P43351-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453260

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

723272

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.0000224

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86208

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45030

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111918

Other (OTH)

AF:

0.00

AC:

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.3

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.046

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.27

LIST_S2

Benign

0.30

M_CAP

Benign

0.0082

MetaRNN

Benign

0.046

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PhyloP100

0.038

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.48

REVEL

Benign

0.092

Sift

Benign

0.36

Sift4G

Benign

0.58

Polyphen

0.20

Vest4

0.084

MutPred

0.050

Loss of methylation at K286 (P = 0.0945)

MVP

0.35

MPC

0.10

ClinPred

0.096

GERP RS

-0.024

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.053

gMVP

0.032

Mutation Taster

=91/9

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00020

dbscSNV1_RF

Benign

0.048

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over