rs2735384

Variant names:

• chr8-89936045-C-T
• rs2735384
• NM_002485.5:c.2235-433G>A

Variant summary

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

The NM_002485.5(NBN):​c.2235-433G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 368,842 control chromosomes in the GnomAD database, including 18,291 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 0.30 (7057 hom., cov: 30)
  • Exomes 𝑓: 0.31 (11234 hom.)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.59

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=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.2235-433G>A		intron_variant	Intron 15 of 15	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.2235-433G>A		intron_variant	Intron 15 of 15	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.305 AC: 45885 AN: 150520 Hom.: 7053 Cov.: 30

Gnomad AFR AF: 0.260

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.286

Gnomad ASJ AF: 0.260

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.297

Gnomad MID AF: 0.269

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.300

GnomAD3 exomes AF: 0.294 AC: 15503 AN: 52762 Hom.: 2438 AF XY: 0.296 AC XY: 8561 AN XY: 28922

Gnomad AFR exome AF: 0.236

Gnomad AMR exome AF: 0.261

Gnomad ASJ exome AF: 0.240

Gnomad EAS exome AF: 0.402

Gnomad SAS exome AF: 0.283

Gnomad FIN exome AF: 0.268

Gnomad NFE exome AF: 0.301

Gnomad OTH exome AF: 0.292

GnomAD4 exome AF: 0.311 AC: 67933 AN: 218242 Hom.: 11234 Cov.: 0 AF XY: 0.312 AC XY: 39614 AN XY: 127084

Gnomad4 AFR exome AF: 0.239

Gnomad4 AMR exome AF: 0.268

Gnomad4 ASJ exome AF: 0.241

Gnomad4 EAS exome AF: 0.394

Gnomad4 SAS exome AF: 0.296

Gnomad4 FIN exome AF: 0.308

Gnomad4 NFE exome AF: 0.322

Gnomad4 OTH exome AF: 0.311

GnomAD4 genome AF: 0.305 AC: 45904 AN: 150600 Hom.: 7057 Cov.: 30 AF XY: 0.303 AC XY: 22259 AN XY: 73342

Gnomad4 AFR AF: 0.259

Gnomad4 AMR AF: 0.286

Gnomad4 ASJ AF: 0.260

Gnomad4 EAS AF: 0.405

Gnomad4 SAS AF: 0.319

Gnomad4 FIN AF: 0.297

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.297

Alfa AF: 0.304 Hom.: 1529

Bravo AF: 0.299

Asia WGS AF: 0.307 AC: 1070 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.75
DANN	Benign	0.17

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: rs2735384; hg19: chr8-90948273; COSMIC: COSV55372525;