rs1805826

chr8-89970328-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.896+36G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0427 in 1,508,190 control chromosomes in the GnomAD database, including 2,808 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (273 hom., cov: 32)
  • Exomes 𝑓: 0.043 (2535 hom.)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.364

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=-0.87).
• BP6: Variant 8-89970328-C-T is Benign according to our data. Variant chr8-89970328-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1243368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.896+36G>A		intron_variant		ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.896+36G>A		intron_variant		1	NM_002485.5	P1

Frequencies

GnomAD3 genomes AF: 0.0427 AC: 6473 AN: 151448 Hom.: 272 Cov.: 32

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.0734

Gnomad FIN AF: 0.0779

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0411

GnomAD3 exomes AF: 0.0712 AC: 17475 AN: 245514 Hom.: 1222 AF XY: 0.0658 AC XY: 8756 AN XY: 133030

Gnomad AFR exome AF: 0.00955

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.0199

Gnomad EAS exome AF: 0.181

Gnomad SAS exome AF: 0.0682

Gnomad FIN exome AF: 0.0764

Gnomad NFE exome AF: 0.0291

Gnomad OTH exome AF: 0.0573

GnomAD4 exome AF: 0.0427 AC: 57907 AN: 1356624 Hom.: 2535 Cov.: 21 AF XY: 0.0428 AC XY: 29153 AN XY: 680462

Gnomad4 AFR exome AF: 0.00826

Gnomad4 AMR exome AF: 0.184

Gnomad4 ASJ exome AF: 0.0194

Gnomad4 EAS exome AF: 0.193

Gnomad4 SAS exome AF: 0.0682

Gnomad4 FIN exome AF: 0.0722

Gnomad4 NFE exome AF: 0.0290

Gnomad4 OTH exome AF: 0.0430

GnomAD4 genome AF: 0.0428 AC: 6480 AN: 151566 Hom.: 273 Cov.: 32 AF XY: 0.0479 AC XY: 3553 AN XY: 74108

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.110

Gnomad4 ASJ AF: 0.0159

Gnomad4 EAS AF: 0.187

Gnomad4 SAS AF: 0.0739

Gnomad4 FIN AF: 0.0779

Gnomad4 NFE AF: 0.0304

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0332 Hom.: 27

Bravo AF: 0.0465

Asia WGS AF: 0.137 AC: 473 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied by a panel of primary immunodeficiencies. Number of patients: 21. Only high quality variants are reported. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Hereditary breast ovarian cancer syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	1.0
Dann	Benign	0.50

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: rs1805826; hg19: chr8-90982556; COSMIC: COSV104545383; COSMIC: COSV104545383;