rs2735384

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 publications found

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]

NBN Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• idiopathic aplastic anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -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

GnomAD2 exomes AF: 0.294 AC: 15503 AN: 52762 AF XY: 0.296

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 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

African (AFR) AF: 0.239 AC: 1019 AN: 4272

American (AMR) AF: 0.268 AC: 2697 AN: 10064

Ashkenazi Jewish (ASJ) AF: 0.241 AC: 1473 AN: 6108

East Asian (EAS) AF: 0.394 AC: 2684 AN: 6804

South Asian (SAS) AF: 0.296 AC: 12785 AN: 43138

European-Finnish (FIN) AF: 0.308 AC: 2906 AN: 9430

Middle Eastern (MID) AF: 0.296 AC: 695 AN: 2350

European-Non Finnish (NFE) AF: 0.322 AC: 40497 AN: 125852

Other (OTH) AF: 0.311 AC: 3177 AN: 10224

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

African (AFR) AF: 0.259 AC: 10633 AN: 40994

American (AMR) AF: 0.286 AC: 4310 AN: 15076

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 902 AN: 3466

East Asian (EAS) AF: 0.405 AC: 2062 AN: 5090

South Asian (SAS) AF: 0.319 AC: 1529 AN: 4788

European-Finnish (FIN) AF: 0.297 AC: 2996 AN: 10084

Middle Eastern (MID) AF: 0.283 AC: 81 AN: 286

European-Non Finnish (NFE) AF: 0.331 AC: 22464 AN: 67820

Other (OTH) AF: 0.297 AC: 620 AN: 2086

Alfa AF: 0.303 Hom.: 1559

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
PhyloP100		-1.6
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: rs2735384; hg19: chr8-90948273; COSMIC: COSV55372525;