dbSNP rs2735385: NBN:c.2185-421G>T (chr8-89937496-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002485.5(NBN):c.2185-421G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 195,152 control chromosomes in the GnomAD database, including 9,542 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 7495 hom., cov: 32)

Exomes 𝑓: 0.29 ( 2047 hom. )

Consequence

NBN
NM_002485.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0870

Publications

16 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.2185-421G>T		intron_variant	Intron 14 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.2185-421G>T		intron_variant	Intron 14 of 15	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.314

AC:

47696

AN:

151954

Hom.:

7486

Cov.:

show subpopulations

Gnomad AFR

AF:

0.288

Gnomad AMI

AF:

0.338

Gnomad AMR

AF:

0.292

Gnomad ASJ

AF:

0.261

Gnomad EAS

AF:

0.407

Gnomad SAS

AF:

0.318

Gnomad FIN

AF:

0.305

Gnomad MID

AF:

0.271

Gnomad NFE

AF:

0.331

Gnomad OTH

AF:

0.307

GnomAD4 exome

AF:

0.289

AC:

12446

AN:

43078

Hom.:

2047

AF XY:

0.287

AC XY:

6546

AN XY:

22824

show subpopulations

African (AFR)

AF:

0.224

AC:

163

AN:

728

American (AMR)

AF:

0.295

AC:

1004

AN:

3398

Ashkenazi Jewish (ASJ)

AF:

0.206

AC:

191

AN:

928

East Asian (EAS)

AF:

0.385

AC:

882

AN:

2292

South Asian (SAS)

AF:

0.262

AC:

1641

AN:

6270

European-Finnish (FIN)

AF:

0.267

AC:

407

AN:

1522

Middle Eastern (MID)

AF:

0.263

AC:

AN:

152

European-Non Finnish (NFE)

AF:

0.293

AC:

7489

AN:

25576

Other (OTH)

AF:

0.284

AC:

629

AN:

2212

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

403

807

1210

1614

2017

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

208

312

416

520

<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:

0.314

AC:

47731

AN:

152074

Hom.:

7495

Cov.:

AF XY:

0.313

AC XY:

23259

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.288

AC:

11928

AN:

41482

American (AMR)

AF:

0.292

AC:

4465

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.261

AC:

905

AN:

3470

East Asian (EAS)

AF:

0.407

AC:

2100

AN:

5164

South Asian (SAS)

AF:

0.320

AC:

1543

AN:

4822

European-Finnish (FIN)

AF:

0.305

AC:

3227

AN:

10582

Middle Eastern (MID)

AF:

0.284

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.332

AC:

22531

AN:

67960

Other (OTH)

AF:

0.304

AC:

641

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1711

3422

5132

6843

8554

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

482

964

1446

1928

2410

<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:

0.322

Hom.:

6723

Bravo

AF:

0.307

Asia WGS

AF:

0.309

AC:

1077

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

1.4

(source)

DANN

Benign

0.58

PhyloP100

0.087

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over