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GeneBe

rs1805794

Variant summary

Our verdict is Benign. Variant got -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. 14/19 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

18

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:17O: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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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/exons MANE UniProt
NBNNM_002485.5 linkuse as main transcriptc.553G>C p.Glu185Gln missense_variant 5/16 ENST00000265433.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NBNENST00000265433.8 linkuse as main transcriptc.553G>C p.Glu185Gln missense_variant 5/161 NM_002485.5 P1

Frequencies

GnomAD3 genomes
AF:
0.310
AC:
47148
AN:
151878
Hom.:
7536
Cov.:
32
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
GnomAD3 exomes
AF:
0.347
AC:
87154
AN:
251200
Hom.:
15452
AF XY:
0.351
AC XY:
47622
AN XY:
135774
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 SAS exome
AF:
0.428
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.:
31
AF XY:
0.334
AC XY:
241069
AN XY:
721132
show subpopulations
Gnomad4 AFR exome
AF:
0.236
Gnomad4 AMR exome
AF:
0.354
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:
0.337
GnomAD4 genome
AF:
0.310
AC:
47188
AN:
151996
Hom.:
7545
Cov.:
32
AF XY:
0.316
AC XY:
23486
AN XY:
74298
show subpopulations
Gnomad4 AFR
AF:
0.237
Gnomad4 AMR
AF:
0.342
Gnomad4 ASJ
AF:
0.308
Gnomad4 EAS
AF:
0.452
Gnomad4 SAS
AF:
0.437
Gnomad4 FIN
AF:
0.353
Gnomad4 NFE
AF:
0.322
Gnomad4 OTH
AF:
0.329
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:17Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:7Other:1
Benign, no assertion criteria providedclinical testingClinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center-- -
Benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMar 28, 2016Variant 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 -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
Benign, criteria provided, single submitterclinical testingUnidad de Genómica Garrahan, Hospital de Pediatría GarrahanJan 24, 2024This 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. -
not provided, no classification providedreference populationITMISep 19, 2013- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Mar 30, 2015- -
Microcephaly, normal intelligence and immunodeficiency Benign:5
Benign, criteria provided, single submitterclinical testingIntelligeneCGAug 18, 2017- -
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabJul 01, 2021- -
Benign, no assertion criteria providedclinical testingNatera, Inc.Sep 16, 2020- -
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaMar 06, 2018This 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 submitterclinical testingInvitaeFeb 01, 2024- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesNov 30, 2023- -
Benign, criteria provided, single submitterclinical testingGeneDxMar 03, 2015This 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
Benign, criteria provided, single submitterclinical testingKCCC/NGS Laboratory, Kuwait Cancer Control CenterJul 07, 2023- -
Hereditary cancer-predisposing syndrome Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsNov 21, 2014This 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 submitterclinical testingNational Health Laboratory Service, Universitas Academic Hospital and University of the Free StateApr 19, 2022- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.056
BayesDel_addAF
Benign
-0.61
T
BayesDel_noAF
Benign
-0.51
Cadd
Benign
14
Dann
Benign
0.15
DEOGEN2
Benign
0.082
T;T;.
Eigen
Benign
-0.82
Eigen_PC
Benign
-0.55
FATHMM_MKL
Benign
0.086
N
LIST_S2
Benign
0.084
T;T;T
MetaRNN
Benign
0.0024
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
-1.2
N;.;.
MutationTaster
Benign
1.0
P;P
PrimateAI
Benign
0.28
T
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
T
GERP RS
3.1
Varity_R
0.059
gMVP
0.28

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.

Other links and lift over

dbSNP: rs1805794; hg19: chr8-90990479; COSMIC: COSV55371261; COSMIC: COSV55371261; API