dbSNP rs61754966: NBN:p.Ile171Val (chr8-89978293-T-C) – 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.511A>G(p.Ile171Val) variant causes a missense change. The variant allele was found at a frequency of 0.00115 in 1,593,902 control chromosomes in the GnomAD database, including 6 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. I171L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0014 ( 1 hom., cov: 33)

Exomes 𝑓: 0.0011 ( 5 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:17B:10O:2

Conservation

PhyloP100: 4.37

Publications

97 publications found

Variant links:

COSMIC-nc: COSV104545444

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=0.037225217).

BP6

Variant 8-89978293-T-C is Benign according to our data. Variant chr8-89978293-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 6946.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00139 (212/152314) while in subpopulation NFE AF = 0.00254 (173/68022). AF 95% confidence interval is 0.00223. There are 1 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 5 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.511A>G	p.Ile171Val	missense	Exon 5 of 16	NP_002476.2
NBN	NM_001024688.3		c.265A>G	p.Ile89Val	missense	Exon 6 of 17	NP_001019859.1
NBN	NM_001440379.1		c.265A>G	p.Ile89Val	missense	Exon 5 of 16	NP_001427308.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NBN	ENST00000265433.8	TSL:1 MANE Select	c.511A>G	p.Ile171Val	missense	Exon 5 of 16	ENSP00000265433.4
NBN	ENST00000697309.1		c.511A>G	p.Ile171Val	missense	Exon 5 of 15	ENSP00000513244.1
NBN	ENST00000697293.1		c.511A>G	p.Ile171Val	missense	Exon 5 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes

AF:

0.00139

AC:

212

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00254

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00120

AC:

301

AN:

251288

AF XY:

0.00117

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.000202

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00152

Gnomad FIN exome

AF:

0.00120

Gnomad NFE exome

AF:

0.00196

Gnomad OTH exome

AF:

0.000979

GnomAD4 exome

AF:

0.00112

AC:

1618

AN:

1441588

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

821

AN XY:

718462

show subpopulations

African (AFR)

AF:

0.0000909

AC:

AN:

33000

American (AMR)

AF:

0.000336

AC:

AN:

44698

Ashkenazi Jewish (ASJ)

AF:

0.000231

AC:

AN:

26004

East Asian (EAS)

AF:

0.00327

AC:

129

AN:

39478

South Asian (SAS)

AF:

0.0000350

AC:

AN:

85778

European-Finnish (FIN)

AF:

0.00157

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.00121

AC:

1325

AN:

1093770

Other (OTH)

AF:

0.000871

AC:

AN:

59726

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

157

236

314

393

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

128

160

<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:

0.00139

AC:

212

AN:

152314

Hom.:

Cov.:

AF XY:

0.00144

AC XY:

107

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.000265

AC:

AN:

41566

American (AMR)

AF:

0.000327

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00173

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00122

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00254

AC:

173

AN:

68022

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.00183

Hom.:

Bravo

AF:

0.000907

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00163

AC:

ExAC

AF:

0.00139

AC:

169

Asia WGS

AF:

0.00144

AC:

AN:

3476

EpiCase

AF:

0.000927

EpiControl

AF:

0.00119

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

Hereditary cancer-predisposing syndrome (5)

Microcephaly, normal intelligence and immunodeficiency (4)

not specified (4)

Acute lymphoid leukemia (1)

Aplastic anemia (1)

Breast carcinoma (1)

Carcinoma of colon (1)

Diffuse midline glioma, H3 K27-altered (1)

Hereditary breast ovarian cancer syndrome (1)

Hereditary cancer (1)

NBN-related disorder (1)

Pediatric high-grade glioma (1)

Leukemia, acute lymphoblastic, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.15

Eigen

Uncertain

0.40

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

M_CAP

Benign

0.019

MetaRNN

Benign

0.037

MetaSVM

Benign

-0.55

MutationAssessor

Pathogenic

3.0

PhyloP100

4.4

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.80

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.40

MVP

0.68

MPC

0.087

ClinPred

0.11

GERP RS

4.8

Varity_R

0.39

gMVP

0.53

Mutation Taster

=16/84

disease causing

(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