8-89943130-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002485.5(NBN):c.2184+123G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 928,244 control chromosomes in the GnomAD database, including 55,784 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8324 hom., cov: 30)
  • Exomes 𝑓: 0.35 (47460 hom.)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.155

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 8-89943130-C-T is Benign according to our data. Variant chr8-89943130-C-T is described in ClinVar as [Benign]. Clinvar id is 1177037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.2184+123G>A		intron_variant		ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.2184+123G>A		intron_variant		1	NM_002485.5	P1

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50003 AN: 150016 Hom.: 8315 Cov.: 30

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.337

GnomAD4 exome AF: 0.345 AC: 268767 AN: 778118 Hom.: 47460 AF XY: 0.349 AC XY: 142737 AN XY: 409236

Gnomad4 AFR exome AF: 0.314

Gnomad4 AMR exome AF: 0.361

Gnomad4 ASJ exome AF: 0.319

Gnomad4 EAS exome AF: 0.485

Gnomad4 SAS exome AF: 0.429

Gnomad4 FIN exome AF: 0.362

Gnomad4 NFE exome AF: 0.325

Gnomad4 OTH exome AF: 0.349

GnomAD4 genome AF: 0.333 AC: 50037 AN: 150126 Hom.: 8324 Cov.: 30 AF XY: 0.338 AC XY: 24786 AN XY: 73306

Gnomad4 AFR AF: 0.315

Gnomad4 AMR AF: 0.352

Gnomad4 ASJ AF: 0.315

Gnomad4 EAS AF: 0.451

Gnomad4 SAS AF: 0.438

Gnomad4 FIN AF: 0.356

Gnomad4 NFE AF: 0.322

Gnomad4 OTH AF: 0.341

Alfa AF: 0.156 Hom.: 306

Bravo AF: 0.326

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 01, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	2.0
Dann	Benign	0.21

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: rs7840099; hg19: chr8-90955358; COSMIC: COSV55372468; COSMIC: COSV55372468;