5-132609272-CTT-CTTT

Variant names:

• chr5-132609272-C-CT
• rs2066742
• NM_005732.4:c.2923-5dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005732.4(RAD50):​c.2923-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,609,978 control chromosomes in the GnomAD database, including 2,235 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (1126 hom., cov: 31)
  • Exomes 𝑓: 0.0094 (1109 hom.)
• Consequence: RAD50 NM_005732.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.01
• Publications: 3 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 -16 ACMG points.

• BP6: Variant 5-132609272-C-CT is Benign according to our data. Variant chr5-132609272-C-CT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 140787.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.228 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	NM_005732.4	MANE Select	c.2923-5dupT		splice_region intron	N/A	NP_005723.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RAD50	ENST00000378823.8	TSL:1 MANE Select	c.2923-11_2923-10insT		intron	N/A	ENSP00000368100.4
	ENSG00000283782	ENST00000638452.2	TSL:5	c.2626-11_2626-10insT		intron	N/A	ENSP00000492349.2
	RAD50	ENST00000533482.5	TSL:1	n.*2549-11_*2549-10insT		intron	N/A	ENSP00000431225.1

Frequencies

GnomAD3 genomes AF: 0.0687 AC: 10440 AN: 151954 Hom.: 1123 Cov.: 31

Gnomad AFR AF: 0.232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0281

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00337

Gnomad OTH AF: 0.0513

GnomAD2 exomes AF: 0.0199 AC: 4902 AN: 246788 AF XY: 0.0158

Gnomad AFR exome AF: 0.239

Gnomad AMR exome AF: 0.0151

Gnomad ASJ exome AF: 0.00232

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00330

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00937 AC: 13661 AN: 1457906 Hom.: 1109 Cov.: 31 AF XY: 0.00863 AC XY: 6256 AN XY: 725028

African (AFR) AF: 0.242 AC: 8032 AN: 33160

American (AMR) AF: 0.0166 AC: 733 AN: 44230

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26038

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39552

South Asian (SAS) AF: 0.00816 AC: 692 AN: 84802

European-Finnish (FIN) AF: 0.000150 AC: 8 AN: 53302

Middle Eastern (MID) AF: 0.0301 AC: 173 AN: 5746

European-Non Finnish (NFE) AF: 0.00260 AC: 2883 AN: 1110856

Other (OTH) AF: 0.0182 AC: 1099 AN: 60220

GnomAD4 genome AF: 0.0688 AC: 10462 AN: 152072 Hom.: 1126 Cov.: 31 AF XY: 0.0666 AC XY: 4953 AN XY: 74342

African (AFR) AF: 0.232 AC: 9621 AN: 41464

American (AMR) AF: 0.0281 AC: 429 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.0116 AC: 56 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.00335 AC: 228 AN: 67970

Other (OTH) AF: 0.0508 AC: 107 AN: 2106

Alfa AF: 0.0320 Hom.: 85

Bravo AF: 0.0801

Asia WGS AF: 0.0190 AC: 65 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
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: rs2066742; hg19: chr5-131944964;