dbSNP rs3026271: NBN:c.702+149T>C (chr8-89971024-A-G) – ACMG Classification: Benign (-20 pts)

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.702+149T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0531 in 728,674 control chromosomes in the GnomAD database, including 1,341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.043 ( 222 hom., cov: 32)

Exomes 𝑓: 0.056 ( 1119 hom. )

Consequence

NBN
NM_002485.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.71

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: 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 8-89971024-A-G is Benign according to our data. Variant chr8-89971024-A-G is described in ClinVar as Benign. ClinVar VariationId is 1263646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0655 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	Effect	Exon Rank	Protein	UniProt
NBN	NM_002485.5	MANE Select	c.702+149T>C	intron	N/A	NP_002476.2
NBN	NM_001024688.3		c.456+149T>C	intron	N/A	NP_001019859.1	A0A0C4DG07
NBN	NM_001440379.1		c.456+149T>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.702+149T>C	intron	N/A	ENSP00000265433.4	O60934
NBN	ENST00000697309.1		c.702+149T>C	intron	N/A	ENSP00000513244.1	A0A8V8TKY5
NBN	ENST00000697293.1		c.702+149T>C	intron	N/A	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes

AF:

0.0432

AC:

6575

AN:

152174

Hom.:

222

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0105

Gnomad AMI

AF:

0.0526

Gnomad AMR

AF:

0.0373

Gnomad ASJ

AF:

0.0444

Gnomad EAS

AF:

0.000770

Gnomad SAS

AF:

0.0315

Gnomad FIN

AF:

0.0521

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0672

Gnomad OTH

AF:

0.0320

GnomAD4 exome

AF:

0.0557

AC:

32123

AN:

576382

Hom.:

1119

AF XY:

0.0551

AC XY:

16667

AN XY:

302258

show subpopulations

African (AFR)

AF:

0.0120

AC:

178

AN:

14772

American (AMR)

AF:

0.0337

AC:

680

AN:

20186

Ashkenazi Jewish (ASJ)

AF:

0.0458

AC:

663

AN:

14472

East Asian (EAS)

AF:

0.000170

AC:

AN:

29462

South Asian (SAS)

AF:

0.0420

AC:

2082

AN:

49578

European-Finnish (FIN)

AF:

0.0470

AC:

1326

AN:

28222

Middle Eastern (MID)

AF:

0.0605

AC:

128

AN:

2114

European-Non Finnish (NFE)

AF:

0.0657

AC:

25520

AN:

388500

Other (OTH)

AF:

0.0530

AC:

1541

AN:

29076

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1468

2936

4403

5871

7339

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

480

960

1440

1920

2400

<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:

0.0431

AC:

6571

AN:

152292

Hom.:

222

Cov.:

AF XY:

0.0423

AC XY:

3147

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0105

AC:

435

AN:

41576

American (AMR)

AF:

0.0371

AC:

568

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0444

AC:

154

AN:

3468

East Asian (EAS)

AF:

0.000771

AC:

AN:

5186

South Asian (SAS)

AF:

0.0315

AC:

152

AN:

4828

European-Finnish (FIN)

AF:

0.0521

AC:

553

AN:

10612

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0672

AC:

4568

AN:

68000

Other (OTH)

AF:

0.0312

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

310

619

929

1238

1548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

156

234

312

390

<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:

0.0501

Hom.:

Bravo

AF:

0.0409

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.6

(source)

DANN

Benign

0.32

PhyloP100

1.7

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over