Genetic Variant NBN:p.Arg215Trp (chr8-89971232-G-A) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002485.5(NBN):c.643C>T(p.Arg215Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00306 in 1,613,094 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0032 ( 11 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:8B:14O:3

Conservation

PhyloP100: 1.63

Publications

80 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05029258).

BP6

Variant 8-89971232-G-A is Benign according to our data. Variant chr8-89971232-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 6948.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00204 (310/152148) while in subpopulation NFE AF = 0.00359 (244/67988). AF 95% confidence interval is 0.00322. There are 0 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 11 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	HGVSp	Effect	Exon Rank	Protein
NBN	NM_002485.5	MANE Select	c.643C>T	p.Arg215Trp	missense	Exon 6 of 16	NP_002476.2
NBN	NM_001024688.3		c.397C>T	p.Arg133Trp	missense	Exon 7 of 17	NP_001019859.1
NBN	NM_001440379.1		c.397C>T	p.Arg133Trp	missense	Exon 6 of 16	NP_001427308.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NBN	ENST00000265433.8	TSL:1 MANE Select	c.643C>T	p.Arg215Trp	missense	Exon 6 of 16	ENSP00000265433.4
NBN	ENST00000697309.1		c.643C>T	p.Arg215Trp	missense	Exon 6 of 15	ENSP00000513244.1
NBN	ENST00000697293.1		c.643C>T	p.Arg215Trp	missense	Exon 6 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes

AF:

0.00204

AC:

310

AN:

152030

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00138

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00199

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00359

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00251

AC:

630

AN:

250856

AF XY:

0.00251

show subpopulations

Gnomad AFR exome

AF:

0.000309

Gnomad AMR exome

AF:

0.00165

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00333

Gnomad NFE exome

AF:

0.00422

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00317

AC:

4624

AN:

1460946

Hom.:

Cov.:

AF XY:

0.00302

AC XY:

2195

AN XY:

726782

show subpopulations

African (AFR)

AF:

0.000508

AC:

AN:

33432

American (AMR)

AF:

0.00168

AC:

AN:

44678

Ashkenazi Jewish (ASJ)

AF:

0.000192

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39590

South Asian (SAS)

AF:

0.000104

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00274

AC:

146

AN:

53328

Middle Eastern (MID)

AF:

0.000695

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00380

AC:

4227

AN:

1111474

Other (OTH)

AF:

0.00234

AC:

141

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

256

511

767

1022

1278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

160

320

480

640

800

<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:

0.00204

AC:

310

AN:

152148

Hom.:

Cov.:

AF XY:

0.00207

AC XY:

154

AN XY:

74368

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

41512

American (AMR)

AF:

0.00137

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00199

AC:

AN:

10578

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00359

AC:

244

AN:

67988

Other (OTH)

AF:

0.00142

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00231

Hom.:

Bravo

AF:

0.00198

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00293

AC:

355

EpiCase

AF:

0.00349

EpiControl

AF:

0.00439

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Microcephaly, normal intelligence and immunodeficiency (9)

not provided (7)

Hereditary cancer-predisposing syndrome (5)

not specified (3)

Breast-ovarian cancer, familial, susceptibility to, 2 (1)

NBN-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Uncertain

0.040

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.53

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.42

FATHMM_MKL

Benign

0.097

LIST_S2

Uncertain

0.95

M_CAP

Benign

0.048

MetaRNN

Benign

0.050

MetaSVM

Uncertain

0.054

MutationAssessor

Uncertain

2.4

PhyloP100

1.6

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-4.1

REVEL

Uncertain

0.34

Sift

Uncertain

0.015

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.63

MVP

0.92

MPC

0.41

ClinPred

0.049

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.56

Mutation Taster

=90/10

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