chr8-89947856-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002485.5(NBN):c.1882G>A(p.Glu628Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000784 in 1,582,686 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E628E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0043 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00041 ( 5 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 0.247

Publications

6 publications found

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 Gene-Disease associations (from GenCC):

Nijmegen breakage syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
idiopathic aplastic anemia
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

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=0.0023639798).

BP6

Variant 8-89947856-C-T is Benign according to our data. Variant chr8-89947856-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 132690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00427 (649/152120) while in subpopulation AFR AF = 0.0149 (619/41502). AF 95% confidence interval is 0.0139. There are 2 homozygotes in GnomAd4. There are 313 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.1882G>A	p.Glu628Lys	missense_variant	Exon 12 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.1882G>A	p.Glu628Lys	missense_variant	Exon 12 of 16	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.00422

AC:

642

AN:

152002

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0148

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.000900

AC:

211

AN:

234420

AF XY:

0.000631

show subpopulations

Gnomad AFR exome

AF:

0.0125

Gnomad AMR exome

AF:

0.000717

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000289

Gnomad OTH exome

AF:

0.00104

GnomAD4 exome

AF:

0.000414

AC:

592

AN:

1430566

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

285

AN XY:

712128

show subpopulations

African (AFR)

AF:

0.0142

AC:

463

AN:

32642

American (AMR)

AF:

0.000797

AC:

AN:

43910

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25452

East Asian (EAS)

AF:

0.00

AC:

AN:

39234

South Asian (SAS)

AF:

0.0000357

AC:

AN:

84136

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52412

Middle Eastern (MID)

AF:

0.000526

AC:

AN:

5700

European-Non Finnish (NFE)

AF:

0.0000202

AC:

AN:

1087996

Other (OTH)

AF:

0.00112

AC:

AN:

59084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.413

Heterozygous variant carriers

117

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00427

AC:

649

AN:

152120

Hom.:

Cov.:

AF XY:

0.00421

AC XY:

313

AN XY:

74378

show subpopulations

African (AFR)

AF:

0.0149

AC:

619

AN:

41502

American (AMR)

AF:

0.00124

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5172

South Asian (SAS)

AF:

0.000207

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10570

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67988

Other (OTH)

AF:

0.00285

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00175

Hom.:

Bravo

AF:

0.00482

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00112

AC:

135

Asia WGS

AF:

0.00231

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 02, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Apr 24, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NBN c.1882G>A (p.Glu628Lys) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00088 in 241282 control chromosomes, predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 96 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1882G>A has been reported in the literature in individuals who underwent testing for Hereditary Breast and Ovarian Cancer and/or Lynch Syndrome, without strong evidence for causality (examples- Haiman_2013, Yorczyk_2015, Yurgelun_2015, Tung_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign (n=5)/likely benign (n=3). Based on the evidence outlined above, the variant was classified as benign. -

Nov 22, 2016

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:5

Aug 15, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 22, 2015

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 22, 2019

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NBN: BP4, BS1 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Microcephaly, normal intelligence and immunodeficiency

Benign:3

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency

Benign:2

Nov 14, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 31, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Jul 23, 2015

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 02, 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. -

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 breast ovarian cancer syndrome

Benign:1

Apr 19, 2022

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.7

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.051

T;T;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.64

T;T;T

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;.;.

PhyloP100

0.25

PrimateAI

Benign

0.30

PROVEAN

Benign

0.30

N;N;.

REVEL

Benign

0.029

Sift

Benign

0.82

T;T;.

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.11

MVP

0.38

MPC

0.075

ClinPred

0.0023

GERP RS

-6.9

Varity_R

0.019

gMVP

0.10

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.20

Position offset: -32

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over