Genetic Variant NM_002485.5:c.2184+311C>G (chr8-89942942-G-C) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_002485.5(NBN):c.2184+311C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 151,670 control chromosomes in the GnomAD database, including 7,467 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.31 ( 7467 hom., cov: 32)

Consequence

NBN
NM_002485.5 intron

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.960

Publications

4 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.91).

BP6

Variant 8-89942942-G-C is Benign according to our data. Variant chr8-89942942-G-C is described in ClinVar as Benign. ClinVar VariationId is 1272514.Status of the report is criteria_provided_single_submitter, 1 stars.

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	Effect	Exon Rank	Protein	UniProt
NBN	NM_002485.5	MANE Select	c.2184+311C>G	intron	N/A	NP_002476.2
NBN	NM_001024688.3		c.1938+311C>G	intron	N/A	NP_001019859.1	A0A0C4DG07
NBN	NM_001440379.1		c.1938+311C>G	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.2184+311C>G	intron	N/A	ENSP00000265433.4	O60934
NBN	ENST00000697309.1		c.2184+311C>G	intron	N/A	ENSP00000513244.1	A0A8V8TKY5
NBN	ENST00000697293.1		c.2185-103C>G	intron	N/A	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes

AF:

0.309

AC:

46788

AN:

151570

Hom.:

7460

Cov.:

show subpopulations

Gnomad AFR

AF:

0.231

Gnomad AMI

AF:

0.266

Gnomad AMR

AF:

0.341

Gnomad ASJ

AF:

0.308

Gnomad EAS

AF:

0.453

Gnomad SAS

AF:

0.436

Gnomad FIN

AF:

0.355

Gnomad MID

AF:

0.275

Gnomad NFE

AF:

0.322

Gnomad OTH

AF:

0.321

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

GnomAD4 genome

AF:

0.309

AC:

46814

AN:

151670

Hom.:

7467

Cov.:

AF XY:

0.314

AC XY:

23283

AN XY:

74088

show subpopulations

African (AFR)

AF:

0.231

AC:

9544

AN:

41358

American (AMR)

AF:

0.342

AC:

5212

AN:

15258

Ashkenazi Jewish (ASJ)

AF:

0.308

AC:

1068

AN:

3464

East Asian (EAS)

AF:

0.451

AC:

2336

AN:

5174

South Asian (SAS)

AF:

0.438

AC:

2106

AN:

4812

European-Finnish (FIN)

AF:

0.355

AC:

3688

AN:

10400

Middle Eastern (MID)

AF:

0.282

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.322

AC:

21847

AN:

67890

Other (OTH)

AF:

0.326

AC:

687

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1629

3258

4888

6517

8146

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:

0.311

Hom.:

948

Bravo

AF:

0.300

Asia WGS

AF:

0.420

AC:

1459

AN:

3470

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.43

(source)

DANN

Benign

0.70

PhyloP100

-0.96

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over