Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002485.5(NBN):c.102G>A(p.Leu34Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.336 in 1,612,414 control chromosomes in the GnomAD database, including 92,617 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L34L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.33 ( 8479 hom., cov: 32)

Exomes 𝑓: 0.34 ( 84138 hom. )

Consequence

NBN
NM_002485.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: -0.137

Publications

52 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 8-89982791-C-T is Benign according to our data. Variant chr8-89982791-C-T is described in ClinVar as Benign. ClinVar VariationId is 183697.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.137 with no splicing effect.

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.102G>A	p.Leu34Leu	synonymous	Exon 2 of 16	NP_002476.2
NBN	NM_001024688.3		c.-195G>A		5_prime_UTR	Exon 2 of 17	NP_001019859.1
NBN	NM_001440379.1		c.-145G>A		5_prime_UTR	Exon 2 of 16	NP_001427308.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NBN	ENST00000265433.8	TSL:1 MANE Select	c.102G>A	p.Leu34Leu	synonymous	Exon 2 of 16	ENSP00000265433.4
NBN	ENST00000697309.1		c.102G>A	p.Leu34Leu	synonymous	Exon 2 of 15	ENSP00000513244.1
NBN	ENST00000697293.1		c.102G>A	p.Leu34Leu	synonymous	Exon 2 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes

AF:

0.333

AC:

50535

AN:

151880

Hom.:

8469

Cov.:

show subpopulations

Gnomad AFR

AF:

0.314

Gnomad AMI

AF:

0.266

Gnomad AMR

AF:

0.352

Gnomad ASJ

AF:

0.315

Gnomad EAS

AF:

0.453

Gnomad SAS

AF:

0.436

Gnomad FIN

AF:

0.354

Gnomad MID

AF:

0.282

Gnomad NFE

AF:

0.322

Gnomad OTH

AF:

0.343

GnomAD2 exomes

AF:

0.354

AC:

88873

AN:

251400

AF XY:

0.355

show subpopulations

Gnomad AFR exome

AF:

0.318

Gnomad AMR exome

AF:

0.354

Gnomad ASJ exome

AF:

0.321

Gnomad EAS exome

AF:

0.456

Gnomad FIN exome

AF:

0.355

Gnomad NFE exome

AF:

0.325

Gnomad OTH exome

AF:

0.335

GnomAD4 exome

AF:

0.336

AC:

490907

AN:

1460416

Hom.:

84138

Cov.:

AF XY:

0.338

AC XY:

245823

AN XY:

726624

show subpopulations

African (AFR)

AF:

0.318

AC:

10631

AN:

33448

American (AMR)

AF:

0.358

AC:

16028

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.318

AC:

8312

AN:

26110

East Asian (EAS)

AF:

0.480

AC:

19016

AN:

39656

South Asian (SAS)

AF:

0.429

AC:

37021

AN:

86234

European-Finnish (FIN)

AF:

0.362

AC:

19329

AN:

53396

Middle Eastern (MID)

AF:

0.344

AC:

1981

AN:

5764

European-Non Finnish (NFE)

AF:

0.322

AC:

357835

AN:

1110760

Other (OTH)

AF:

0.344

AC:

20754

AN:

60332

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

16819

33637

50456

67274

84093

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11730

23460

35190

46920

58650

<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:

50581

AN:

151998

Hom.:

8479

Cov.:

AF XY:

0.338

AC XY:

25081

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.314

AC:

13000

AN:

41436

American (AMR)

AF:

0.352

AC:

5372

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.315

AC:

1091

AN:

3468

East Asian (EAS)

AF:

0.451

AC:

2333

AN:

5172

South Asian (SAS)

AF:

0.437

AC:

2111

AN:

4826

European-Finnish (FIN)

AF:

0.354

AC:

3726

AN:

10536

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.322

AC:

21886

AN:

67972

Other (OTH)

AF:

0.347

AC:

734

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1743

3486

5228

6971

8714

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:

0.316

Hom.:

12391

Bravo

AF:

0.329

Asia WGS

AF:

0.425

AC:

1479

AN:

3478

EpiCase

AF:

0.319

EpiControl

AF:

0.317

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Microcephaly, normal intelligence and immunodeficiency (5)

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

BayesDel_noAF

Benign

-0.52

CADD

Benign

3.1

(source)

DANN

Benign

0.88

PhyloP100

-0.14

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=300/0

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over