8-89946302-T-C

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.1915-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.333 in 1,566,918 control chromosomes in the GnomAD database, including 88,722 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8458 hom., cov: 32)

Exomes 𝑓: 0.33 ( 80264 hom. )

Consequence

NBN
NM_002485.5 splice_region, intron

Scores

Splicing: ADA: 0.00003018

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:16

Conservation

PhyloP100: -1.93

Publications

21 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 (BayesDel_noAF=-0.92).

BP6

Variant 8-89946302-T-C is Benign according to our data. Variant chr8-89946302-T-C is described in ClinVar as Benign. ClinVar VariationId is 258768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.1915-7A>G		splice_region_variant, intron_variant	Intron 12 of 15	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.1915-7A>G		splice_region_variant, intron_variant	Intron 12 of 15	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.333

AC:

50463

AN:

151730

Hom.:

8448

Cov.:

show subpopulations

Gnomad AFR

AF:

0.314

Gnomad AMI

AF:

0.265

Gnomad AMR

AF:

0.352

Gnomad ASJ

AF:

0.314

Gnomad EAS

AF:

0.453

Gnomad SAS

AF:

0.436

Gnomad FIN

AF:

0.351

Gnomad MID

AF:

0.285

Gnomad NFE

AF:

0.322

Gnomad OTH

AF:

0.342

GnomAD2 exomes

AF:

0.353

AC:

88645

AN:

250770

AF XY:

0.355

show subpopulations

Gnomad AFR exome

AF:

0.319

Gnomad AMR exome

AF:

0.354

Gnomad ASJ exome

AF:

0.321

Gnomad EAS exome

AF:

0.456

Gnomad FIN exome

AF:

0.354

Gnomad NFE exome

AF:

0.325

Gnomad OTH exome

AF:

0.337

GnomAD4 exome

AF:

0.333

AC:

470792

AN:

1415072

Hom.:

80264

Cov.:

AF XY:

0.335

AC XY:

236815

AN XY:

706380

show subpopulations

African (AFR)

AF:

0.314

AC:

10203

AN:

32456

American (AMR)

AF:

0.358

AC:

15986

AN:

44632

Ashkenazi Jewish (ASJ)

AF:

0.317

AC:

8200

AN:

25844

East Asian (EAS)

AF:

0.479

AC:

18798

AN:

39268

South Asian (SAS)

AF:

0.427

AC:

36357

AN:

85126

European-Finnish (FIN)

AF:

0.362

AC:

19223

AN:

53104

Middle Eastern (MID)

AF:

0.342

AC:

1934

AN:

5662

European-Non Finnish (NFE)

AF:

0.318

AC:

339972

AN:

1070034

Other (OTH)

AF:

0.341

AC:

20119

AN:

58946

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

13963

27926

41889

55852

69815

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10958

21916

32874

43832

54790

<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:

0.333

AC:

50508

AN:

151846

Hom.:

8458

Cov.:

AF XY:

0.338

AC XY:

25054

AN XY:

74204

show subpopulations

African (AFR)

AF:

0.314

AC:

13004

AN:

41442

American (AMR)

AF:

0.352

AC:

5367

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.314

AC:

1090

AN:

3466

East Asian (EAS)

AF:

0.452

AC:

2335

AN:

5170

South Asian (SAS)

AF:

0.438

AC:

2109

AN:

4816

European-Finnish (FIN)

AF:

0.351

AC:

3691

AN:

10504

Middle Eastern (MID)

AF:

0.293

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.322

AC:

21853

AN:

67876

Other (OTH)

AF:

0.346

AC:

732

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1729

3458

5188

6917

8646

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

508

1016

1524

2032

2540

<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:

0.324

Hom.:

2958

Bravo

AF:

0.329

Asia WGS

AF:

0.427

AC:

1481

AN:

3470

EpiCase

AF:

0.319

EpiControl

AF:

0.317

ClinVar

Significance: Benign

Submissions summary: Benign:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

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 -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

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 63% of patients studied by a panel of primary immunodeficiencies. Number of patients: 60. Only high quality variants are reported. -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Significance:Benign

Review Status:no assertion criteria provided

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

- -

Microcephaly, normal intelligence and immunodeficiency

Benign:5

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

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

- -

Jan 12, 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. -

not provided

Benign:3

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.077

(source)

DANN

Benign

0.30

PhyloP100

-1.9

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000030

dbscSNV1_RF

Benign

0.036

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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