rs2735385

chr8-89937496-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002485.5(NBN):c.2185-421G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 195,152 control chromosomes in the GnomAD database, including 9,542 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 0.31 (7495 hom., cov: 32)
  • Exomes 𝑓: 0.29 (2047 hom.)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0870

Genes affected

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.2185-421G>T		intron_variant		ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.2185-421G>T		intron_variant		1	NM_002485.5	P1

Frequencies

GnomAD3 genomes AF: 0.314 AC: 47696 AN: 151954 Hom.: 7486 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.307

GnomAD4 exome AF: 0.289 AC: 12446 AN: 43078 Hom.: 2047 AF XY: 0.287 AC XY: 6546 AN XY: 22824

Gnomad4 AFR exome AF: 0.224

Gnomad4 AMR exome AF: 0.295

Gnomad4 ASJ exome AF: 0.206

Gnomad4 EAS exome AF: 0.385

Gnomad4 SAS exome AF: 0.262

Gnomad4 FIN exome AF: 0.267

Gnomad4 NFE exome AF: 0.293

Gnomad4 OTH exome AF: 0.284

GnomAD4 genome AF: 0.314 AC: 47731 AN: 152074 Hom.: 7495 Cov.: 32 AF XY: 0.313 AC XY: 23259 AN XY: 74336

Gnomad4 AFR AF: 0.288

Gnomad4 AMR AF: 0.292

Gnomad4 ASJ AF: 0.261

Gnomad4 EAS AF: 0.407

Gnomad4 SAS AF: 0.320

Gnomad4 FIN AF: 0.305

Gnomad4 NFE AF: 0.332

Gnomad4 OTH AF: 0.304

Alfa AF: 0.323 Hom.: 4973

Bravo AF: 0.307

Asia WGS AF: 0.309 AC: 1077 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
Cadd	Benign	1.4
Dann	Benign	0.58

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: rs2735385; hg19: chr8-90949724;