rs1805794

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002485.5(NBN):c.553G>C(p.Glu185Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,599,778 control chromosomes in the GnomAD database, including 89,101 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E185G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.31 ( 7545 hom., cov: 32)

Exomes 𝑓: 0.33 ( 81556 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:19O:1

Conservation

PhyloP100: 2.21

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024151206).

BP6

Variant 8-89978251-C-G is Benign according to our data. Variant chr8-89978251-C-G is described in ClinVar as [Benign]. Clinvar id is 134876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89978251-C-G is described in Lovd as [Benign].

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 rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.553G>C	p.Glu185Gln	missense_variant	Exon 5 of 16	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.553G>C	p.Glu185Gln	missense_variant	Exon 5 of 16	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.310

AC:

47148

AN:

151878

Hom.:

7536

Cov.:

show subpopulations

Gnomad AFR

AF:

0.237

Gnomad AMI

AF:

0.266

Gnomad AMR

AF:

0.342

Gnomad ASJ

AF:

0.308

Gnomad EAS

AF:

0.453

Gnomad SAS

AF:

0.435

Gnomad FIN

AF:

0.353

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.322

Gnomad OTH

AF:

0.324

GnomAD2 exomes

AF:

0.347

AC:

87154

AN:

251200

AF XY:

0.351

show subpopulations

Gnomad AFR exome

AF:

0.236

Gnomad AMR exome

AF:

0.349

Gnomad ASJ exome

AF:

0.316

Gnomad EAS exome

AF:

0.456

Gnomad FIN exome

AF:

0.354

Gnomad NFE exome

AF:

0.325

Gnomad OTH exome

AF:

0.332

GnomAD4 exome

AF:

0.331

AC:

479880

AN:

1447782

Hom.:

81556

Cov.:

AF XY:

0.334

AC XY:

241069

AN XY:

721132

show subpopulations

Gnomad4 AFR exome

AF:

0.236

AC:

7852

AN:

33214

Gnomad4 AMR exome

AF:

0.354

AC:

15807

AN:

44690

Gnomad4 ASJ exome

AF:

0.312

AC:

8129

AN:

26044

Gnomad4 EAS exome

AF:

0.479

AC:

18922

AN:

39494

Gnomad4 SAS exome

AF:

0.428

AC:

36745

AN:

85854

Gnomad4 FIN exome

AF:

0.362

AC:

19323

AN:

53388

Gnomad4 NFE exome

AF:

0.319

AC:

351002

AN:

1099460

Gnomad4 Remaining exome

AF:

0.337

AC:

20167

AN:

59910

Heterozygous variant carriers

15595

31190

46784

62379

77974

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

11408

22816

34224

45632

57040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.310

AC:

47188

AN:

151996

Hom.:

7545

Cov.:

AF XY:

0.316

AC XY:

23486

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.237

AC:

0.237355

AN:

0.237355

Gnomad4 AMR

AF:

0.342

AC:

0.34194

AN:

0.34194

Gnomad4 ASJ

AF:

0.308

AC:

0.30818

AN:

0.30818

Gnomad4 EAS

AF:

0.452

AC:

0.451625

AN:

0.451625

Gnomad4 SAS

AF:

0.437

AC:

0.437163

AN:

0.437163

Gnomad4 FIN

AF:

0.353

AC:

0.353159

AN:

0.353159

Gnomad4 NFE

AF:

0.322

AC:

0.321932

AN:

0.321932

Gnomad4 OTH

AF:

0.329

AC:

0.328735

AN:

0.328735

Heterozygous variant carriers

1670

3340

5011

6681

8351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

484

968

1452

1936

2420

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.321

Hom.:

6183

Bravo

AF:

0.303

TwinsUK

AF:

0.325

AC:

1205

ALSPAC

AF:

0.325

AC:

1254

ESP6500AA

AF:

0.234

AC:

1030

ESP6500EA

AF:

0.314

AC:

2697

ExAC

AF:

0.345

AC:

41913

Asia WGS

AF:

0.421

AC:

1464

AN:

3478

EpiCase

AF:

0.318

EpiControl

AF:

0.316

ClinVar

Significance: Benign

Submissions summary: Benign:19Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7Other:1

Mar 30, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 19, 2013

ITMI

Significance:not provided

Review Status:no classification provided

Collection Method:reference population

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, variant associated with lung cancer -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Microcephaly, normal intelligence and immunodeficiency

Benign:6

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Aug 18, 2017

IntelligeneCG

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 25, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 28476809, 25771871, 24728327, 27153395, 12917199, 24113799, 21656575, 21166880, 22070649, 19706757, 19393077, 20143155) -

Acute lymphoid leukemia

Benign:1

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:1

Nov 21, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Apr 19, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.15

DEOGEN2

Benign

0.082

T;T;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.084

T;T;T

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.2

N;.;.

PrimateAI

Benign

0.28

PROVEAN

Benign

0.53

N;N;N

REVEL

Benign

0.10

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;.

Polyphen

0.0

B;.;.

Vest4

0.078

MPC

0.067

ClinPred

0.00096

GERP RS

3.1

Varity_R

0.059

gMVP

0.28

Mutation Taster

=96/4

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over