rs1061302

Positions:

• chr8-89946194-T-C
• chr8-89946194-T-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002485.5(NBN):​c.2016A>G​(p.Pro672=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,596,714 control chromosomes in the GnomAD database, including 88,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P672P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.31 (7460 hom., cov: 32)
  • Exomes 𝑓: 0.33 (81121 hom.)
• Consequence: NBN NM_002485.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -2.58

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 8-89946194-T-C is Benign according to our data. Variant chr8-89946194-T-C is described in ClinVar as [Benign]. Clinvar id is 183696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89946194-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.58 with no splicing effect.
• 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.2016A>G	p.Pro672=	synonymous_variant	13/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.2016A>G	p.Pro672=	synonymous_variant	13/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46788 AN: 151810 Hom.: 7452 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.321

GnomAD3 exomes AF: 0.347 AC: 87004 AN: 250934 Hom.: 15425 AF XY: 0.351 AC XY: 47561 AN XY: 135648

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.316

Gnomad EAS exome AF: 0.456

Gnomad SAS exome AF: 0.428

Gnomad FIN exome AF: 0.355

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.331 AC: 478330 AN: 1444786 Hom.: 81121 Cov.: 32 AF XY: 0.334 AC XY: 240316 AN XY: 719804

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.353

Gnomad4 ASJ exome AF: 0.312

Gnomad4 EAS exome AF: 0.479

Gnomad4 SAS exome AF: 0.428

Gnomad4 FIN exome AF: 0.362

Gnomad4 NFE exome AF: 0.319

Gnomad4 OTH exome AF: 0.336

GnomAD4 genome AF: 0.308 AC: 46816 AN: 151928 Hom.: 7460 Cov.: 32 AF XY: 0.314 AC XY: 23276 AN XY: 74238

Gnomad4 AFR AF: 0.230

Gnomad4 AMR AF: 0.341

Gnomad4 ASJ AF: 0.307

Gnomad4 EAS AF: 0.451

Gnomad4 SAS AF: 0.438

Gnomad4 FIN AF: 0.352

Gnomad4 NFE AF: 0.322

Gnomad4 OTH AF: 0.325

Alfa AF: 0.307 Hom.: 9341

Bravo AF: 0.300

Asia WGS AF: 0.421 AC: 1463 AN: 3472

EpiCase AF: 0.318

EpiControl AF: 0.317

ClinVar

Significance: Benign

Submissions summary: Benign:15

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

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 61% of patients studied by a panel of primary immunodeficiencies. Number of patients: 58. Only high quality variants are reported. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Microcephaly, normal intelligence and immunodeficiency Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Acute lymphoid leukemia Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 07, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary breast ovarian cancer syndrome Benign:1

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	-0.86
CADD	Benign	0.47
DANN	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1061302; hg19: chr8-90958422; COSMIC: COSV55371426;