12-916703-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_134424.4(RAD52):c.661C>G(p.Gln221Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,614,186 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0091 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (22 hom.)
• Consequence: RAD52 NM_134424.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.659

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018187463).
• BP6: Variant 12-916703-G-C is Benign according to our data. Variant chr12-916703-G-C is described in ClinVar as [Benign]. Clinvar id is 781058.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00909 (1384/152308) while in subpopulation AFR AF= 0.0312 (1295/41568). AF 95% confidence interval is 0.0297. There are 22 homozygotes in gnomad4. There are 672 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 19 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RAD52	NM_134424.4	c.661C>G	p.Gln221Glu	missense_variant	8/12	ENST00000358495.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RAD52	ENST00000358495.8	c.661C>G	p.Gln221Glu	missense_variant	8/12	1	NM_134424.4	P2

Frequencies

GnomAD3 genomes AF: 0.00900 AC: 1369 AN: 152190 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0309

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00386

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00240 AC: 598 AN: 249254 Hom.: 9 AF XY: 0.00174 AC XY: 236 AN XY: 135272

Gnomad AFR exome AF: 0.0305

Gnomad AMR exome AF: 0.00249

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00107 AC: 1564 AN: 1461878 Hom.: 22 Cov.: 32 AF XY: 0.000945 AC XY: 687 AN XY: 727238

Gnomad4 AFR exome AF: 0.0335

Gnomad4 AMR exome AF: 0.00284

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00909 AC: 1384 AN: 152308 Hom.: 22 Cov.: 32 AF XY: 0.00902 AC XY: 672 AN XY: 74484

Gnomad4 AFR AF: 0.0312

Gnomad4 AMR AF: 0.00386

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00181 Hom.: 4

Bravo AF: 0.0107

ESP6500AA AF: 0.0320 AC: 134

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00282 AC: 342

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.051
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.79
Cadd	Benign	0.17
Dann	Benign	0.093
DEOGEN2	Benign	0.032	T;T;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0040	N
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.7	N;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.79	N;N;N
REVEL	Benign	0.038
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.040
MVP		0.26
MPC		0.12
ClinPred		0.0035	T
GERP RS		-0.73
Varity_R		0.040
gMVP		0.061

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: rs4987206; hg19: chr12-1025869;