chr8-89978251-C-G

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. 16/21 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:20O:1

Conservation

PhyloP100: 2.21

Publications

228 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=0.0024151206).

BP6

Variant 8-89978251-C-G is Benign according to our data. Variant chr8-89978251-C-G is described in ClinVar as Benign. ClinVar VariationId is 134876.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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002485.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NBN	NM_002485.5	MANE Select	c.553G>C	p.Glu185Gln	missense	Exon 5 of 16	NP_002476.2
NBN	NM_001024688.3		c.307G>C	p.Glu103Gln	missense	Exon 6 of 17	NP_001019859.1
NBN	NM_001440379.1		c.307G>C	p.Glu103Gln	missense	Exon 5 of 16	NP_001427308.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NBN	ENST00000265433.8	TSL:1 MANE Select	c.553G>C	p.Glu185Gln	missense	Exon 5 of 16	ENSP00000265433.4
NBN	ENST00000697309.1		c.553G>C	p.Glu185Gln	missense	Exon 5 of 15	ENSP00000513244.1
NBN	ENST00000697293.1		c.553G>C	p.Glu185Gln	missense	Exon 5 of 17	ENSP00000513230.1

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

African (AFR)

AF:

0.236

AC:

7852

AN:

33214

American (AMR)

AF:

0.354

AC:

15807

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.312

AC:

8129

AN:

26044

East Asian (EAS)

AF:

0.479

AC:

18922

AN:

39494

South Asian (SAS)

AF:

0.428

AC:

36745

AN:

85854

European-Finnish (FIN)

AF:

0.362

AC:

19323

AN:

53388

Middle Eastern (MID)

AF:

0.337

AC:

1933

AN:

5728

European-Non Finnish (NFE)

AF:

0.319

AC:

351002

AN:

1099460

Other (OTH)

AF:

0.337

AC:

20167

AN:

59910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.444

Heterozygous variant carriers

15595

31190

46784

62379

77974

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

African (AFR)

AF:

0.237

AC:

9845

AN:

41478

American (AMR)

AF:

0.342

AC:

5218

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

1070

AN:

3472

East Asian (EAS)

AF:

0.452

AC:

2334

AN:

5168

South Asian (SAS)

AF:

0.437

AC:

2108

AN:

4822

European-Finnish (FIN)

AF:

0.353

AC:

3723

AN:

10542

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.322

AC:

21874

AN:

67946

Other (OTH)

AF:

0.329

AC:

691

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1670

3340

5011

6681

8351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

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

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (8)

Microcephaly, normal intelligence and immunodeficiency (6)

not provided (3)

Hereditary cancer-predisposing syndrome (2)

Acute lymphoid leukemia (1)

Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.15

DEOGEN2

Benign

0.082

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.084

MetaRNN

Benign

0.0024

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.2

PhyloP100

2.2

PrimateAI

Benign

0.28

PROVEAN

Benign

0.53

REVEL

Benign

0.10

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over