rs2252775

Variant names:

• chr5-132582752-T-G
• rs2252775
• NM_005732.4:c.756+2686T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005732.4(RAD50):​c.756+2686T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 152,008 control chromosomes in the GnomAD database, including 2,700 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (2700 hom., cov: 32)
• Consequence: RAD50 NM_005732.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0480
• Publications: 14 publications found

Genes affected

RAD50 (HGNC:9816): (RAD50 double strand break repair protein) The protein encoded by this gene is highly similar to Saccharomyces cerevisiae Rad50, a protein involved in DNA double-strand break repair. This protein forms a complex with MRE11 and NBS1. The protein complex binds to DNA and displays numerous enzymatic activities that are required for nonhomologous joining of DNA ends. This protein, cooperating with its partners, is important for DNA double-strand break repair, cell cycle checkpoint activation, telomere maintenance, and meiotic recombination. Knockout studies of the mouse homolog suggest this gene is essential for cell growth and viability. Mutations in this gene are the cause of Nijmegen breakage syndrome-like disorder.[provided by RefSeq, Apr 2010]

RAD50 Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome-like disorder

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000283782 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005732.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	NM_005732.4	MANE Select	c.756+2686T>G		intron	N/A	NP_005723.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	ENST00000378823.8	TSL:1 MANE Select	c.756+2686T>G		intron	N/A	ENSP00000368100.4
	ENSG00000283782	ENST00000638452.2	TSL:5	c.459+2686T>G		intron	N/A	ENSP00000492349.2
	RAD50	ENST00000533482.5	TSL:1	n.*382+2686T>G		intron	N/A	ENSP00000431225.1

Frequencies

GnomAD3 genomes AF: 0.181 AC: 27562 AN: 151890 Hom.: 2696 Cov.: 32

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.122

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.175

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.243

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.215

Gnomad OTH AF: 0.186

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.181 AC: 27569 AN: 152008 Hom.: 2700 Cov.: 32 AF XY: 0.183 AC XY: 13622 AN XY: 74314

African (AFR) AF: 0.116 AC: 4805 AN: 41414

American (AMR) AF: 0.146 AC: 2224 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 808 AN: 3470

East Asian (EAS) AF: 0.176 AC: 908 AN: 5168

South Asian (SAS) AF: 0.225 AC: 1086 AN: 4818

European-Finnish (FIN) AF: 0.243 AC: 2571 AN: 10574

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.215 AC: 14609 AN: 67984

Other (OTH) AF: 0.184 AC: 387 AN: 2104

Alfa AF: 0.204 Hom.: 1226

Bravo AF: 0.168

Asia WGS AF: 0.189 AC: 659 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.0
DANN	Benign	0.49
PhyloP100		0.048
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: rs2252775; hg19: chr5-131918444;