12-926876-C-T

Variant names:

• chr12-926876-C-T
• rs7487683
• ENST00000545564.5:c.538G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000545564.5(RAD52):​c.538G>A​(p.Gly180Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0315 in 1,536,408 control chromosomes in the GnomAD database, including 849 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/16 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.021 (50 hom., cov: 32)
  • Exomes 𝑓: 0.033 (799 hom.)
• Consequence: RAD52 ENST00000545564.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.296
• Publications: 13 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003516376).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0215 (3270/152186) while in subpopulation NFE AF = 0.0343 (2334/68000). AF 95% confidence interval is 0.0332. There are 50 homozygotes in GnomAd4. There are 1490 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RAD52	NM_134424.4	c.467+269G>A		intron_variant	Intron 6 of 11	ENST00000358495.8	NP_602296.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RAD52	ENST00000358495.8	c.467+269G>A		intron_variant	Intron 6 of 11	1	NM_134424.4	ENSP00000351284.3

Frequencies

GnomAD3 genomes AF: 0.0215 AC: 3272 AN: 152068 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.00616

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.0268

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0343

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0219 AC: 3119 AN: 142260 AF XY: 0.0219

Gnomad AFR exome AF: 0.00614

Gnomad AMR exome AF: 0.0187

Gnomad ASJ exome AF: 0.0236

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.0376

Gnomad OTH exome AF: 0.0261

GnomAD4 exome AF: 0.0326 AC: 45103 AN: 1384222 Hom.: 799 Cov.: 33 AF XY: 0.0318 AC XY: 21710 AN XY: 683104

African (AFR) AF: 0.00618 AC: 195 AN: 31578

American (AMR) AF: 0.0192 AC: 687 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.0247 AC: 623 AN: 25178

East Asian (EAS) AF: 0.0000560 AC: 2 AN: 35728

South Asian (SAS) AF: 0.00433 AC: 343 AN: 79222

European-Finnish (FIN) AF: 0.0113 AC: 394 AN: 35000

Middle Eastern (MID) AF: 0.0139 AC: 77 AN: 5538

European-Non Finnish (NFE) AF: 0.0383 AC: 41275 AN: 1078400

Other (OTH) AF: 0.0260 AC: 1507 AN: 57878

GnomAD4 genome AF: 0.0215 AC: 3270 AN: 152186 Hom.: 50 Cov.: 32 AF XY: 0.0200 AC XY: 1490 AN XY: 74400

African (AFR) AF: 0.00614 AC: 255 AN: 41542

American (AMR) AF: 0.0268 AC: 409 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3468

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.00187 AC: 9 AN: 4818

European-Finnish (FIN) AF: 0.0109 AC: 115 AN: 10578

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0343 AC: 2334 AN: 68000

Other (OTH) AF: 0.0256 AC: 54 AN: 2112

Alfa AF: 0.0259 Hom.: 69

Bravo AF: 0.0230

TwinsUK AF: 0.0402 AC: 149

ALSPAC AF: 0.0350 AC: 135

ESP6500AA AF: 0.00730 AC: 20

ESP6500EA AF: 0.0321 AC: 204

ExAC AF: 0.00789 AC: 479

Asia WGS AF: 0.00375 AC: 13 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	5.2
DANN	Benign	0.52
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.063	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
PhyloP100		0.30
PROVEAN	Benign	1.5	N
REVEL	Benign	0.090
Sift	Benign	0.036	D
Sift4G	Benign	0.87	T
Vest4		0.18
MutPred		0.60		Loss of catalytic residue at G180 (P = 0.0242);
ClinPred		0.0051	T
GERP RS		-2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs7487683; hg19: chr12-1036042; COSMIC: COSV57274839; COSMIC: COSV57274839;