Genetic Variant NBN:c.585-1285C>G (chr8-89972575-G-C) – 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.585-1285C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 152,168 control chromosomes in the GnomAD database, including 5,303 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 0.25 ( 5303 hom., cov: 33)

Consequence

NBN
NM_002485.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0670

Publications

7 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=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.585-1285C>G		intron_variant	Intron 5 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.585-1285C>G		intron_variant	Intron 5 of 15	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.248

AC:

37638

AN:

152048

Hom.:

5300

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.257

Gnomad AMR

AF:

0.285

Gnomad ASJ

AF:

0.271

Gnomad EAS

AF:

0.397

Gnomad SAS

AF:

0.338

Gnomad FIN

AF:

0.344

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.293

Gnomad OTH

AF:

0.259

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.247

AC:

37642

AN:

152168

Hom.:

5303

Cov.:

AF XY:

0.254

AC XY:

18897

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.103

AC:

4275

AN:

41546

American (AMR)

AF:

0.285

AC:

4351

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.271

AC:

939

AN:

3466

East Asian (EAS)

AF:

0.396

AC:

2051

AN:

5176

South Asian (SAS)

AF:

0.339

AC:

1634

AN:

4818

European-Finnish (FIN)

AF:

0.344

AC:

3644

AN:

10594

Middle Eastern (MID)

AF:

0.248

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.293

AC:

19897

AN:

67966

Other (OTH)

AF:

0.257

AC:

544

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1430

2860

4289

5719

7149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.174

Hom.:

389

Bravo

AF:

0.233

Asia WGS

AF:

0.312

AC:

1086

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

4.4

(source)

DANN

Benign

0.80

PhyloP100

-0.067

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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8-89972575-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over