Genetic Variant NBN:c.995-2656T>C (chr8-89961510-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_002485.5(NBN):c.995-2656T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 152,296 control chromosomes in the GnomAD database, including 62 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 0.027 ( 62 hom., cov: 32)

Consequence

NBN
NM_002485.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.376

Publications

6 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Orphanet, ClinGen
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=-0.83).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0269 (4096/152296) while in subpopulation NFE AF = 0.039 (2653/68024). AF 95% confidence interval is 0.0378. There are 62 homozygotes in GnomAd4. There are 1981 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 62 AR,AD gene

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	Effect	Exon Rank	Protein	UniProt
NBN	NM_002485.5	MANE Select	c.995-2656T>C	intron	N/A	NP_002476.2
NBN	NM_001024688.3		c.749-2656T>C	intron	N/A	NP_001019859.1	A0A0C4DG07
NBN	NM_001440379.1		c.749-2656T>C	intron	N/A	NP_001427308.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NBN	ENST00000265433.8	TSL:1 MANE Select	c.995-2656T>C	intron	N/A	ENSP00000265433.4	O60934
NBN	ENST00000697309.1		c.995-2656T>C	intron	N/A	ENSP00000513244.1	A0A8V8TKY5
NBN	ENST00000697293.1		c.995-2656T>C	intron	N/A	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes

AF:

0.0269

AC:

4096

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00688

Gnomad AMI

AF:

0.0439

Gnomad AMR

AF:

0.0234

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00911

Gnomad FIN

AF:

0.0528

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0390

Gnomad OTH

AF:

0.0273

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

GnomAD4 genome

AF:

0.0269

AC:

4096

AN:

152296

Hom.:

Cov.:

AF XY:

0.0266

AC XY:

1981

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00688

AC:

286

AN:

41570

American (AMR)

AF:

0.0233

AC:

356

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0268

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5188

South Asian (SAS)

AF:

0.00911

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0528

AC:

560

AN:

10610

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0390

AC:

2653

AN:

68024

Other (OTH)

AF:

0.0270

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

203

406

610

813

1016

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0236

Hom.:

Bravo

AF:

0.0241

Asia WGS

AF:

0.00549

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

6.2

(source)

DANN

Benign

0.76

PhyloP100

0.38

Mutation Taster

=100/0

polymorphism

(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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over