rs1805794

Positions:

chr8-89978251-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002485.5(NBN):c.553G>C(p.Glu185Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,599,778 control chromosomes in the GnomAD database, including 89,101 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7545 hom., cov: 32)

Exomes 𝑓: 0.33 ( 81556 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18O:1

Conservation

PhyloP100: 2.21

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0024151206).

BP6

Variant 8-89978251-C-G is Benign according to our data. Variant chr8-89978251-C-G is described in ClinVar as [Benign]. Clinvar id is 134876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89978251-C-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5 linkuse as main transcript	c.553G>C	p.Glu185Gln	missense_variant	5/16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 linkuse as main transcript	c.553G>C	p.Glu185Gln	missense_variant	5/16	1	NM_002485.5	ENSP00000265433	P1

Frequencies

GnomAD3 genomes

AF:

0.310

AC:

47148

AN:

151878

Hom.:

7536

Cov.:

show subpopulations

Gnomad AFR

AF:

0.237

Gnomad AMI

AF:

0.266

Gnomad AMR

AF:

0.342

Gnomad ASJ

AF:

0.308

Gnomad EAS

AF:

0.453

Gnomad SAS

AF:

0.435

Gnomad FIN

AF:

0.353

Gnomad MID

AF:

0.272

Gnomad NFE

AF:

0.322

Gnomad OTH

AF:

0.324

GnomAD3 exomes

AF:

0.347

AC:

87154

AN:

251200

Hom.:

15452

AF XY:

0.351

AC XY:

47622

AN XY:

135774

show subpopulations

Gnomad AFR exome

AF:

0.236

Gnomad AMR exome

AF:

0.349

Gnomad ASJ exome

AF:

0.316

Gnomad EAS exome

AF:

0.456

Gnomad SAS exome

AF:

0.428

Gnomad FIN exome

AF:

0.354

Gnomad NFE exome

AF:

0.325

Gnomad OTH exome

AF:

0.332

GnomAD4 exome

AF:

0.331

AC:

479880

AN:

1447782

Hom.:

81556

Cov.:

AF XY:

0.334

AC XY:

241069

AN XY:

721132

show subpopulations

Gnomad4 AFR exome

AF:

0.236

Gnomad4 AMR exome

AF:

0.354

Gnomad4 ASJ exome

AF:

0.312

Gnomad4 EAS exome

AF:

0.479

Gnomad4 SAS exome

AF:

0.428

Gnomad4 FIN exome

AF:

0.362

Gnomad4 NFE exome

AF:

0.319

Gnomad4 OTH exome

AF:

0.337

GnomAD4 genome

AF:

0.310

AC:

47188

AN:

151996

Hom.:

7545

Cov.:

AF XY:

0.316

AC XY:

23486

AN XY:

74298

show subpopulations

Gnomad4 AFR

AF:

0.237

Gnomad4 AMR

AF:

0.342

Gnomad4 ASJ

AF:

0.308

Gnomad4 EAS

AF:

0.452

Gnomad4 SAS

AF:

0.437

Gnomad4 FIN

AF:

0.353

Gnomad4 NFE

AF:

0.322

Gnomad4 OTH

AF:

0.329

Alfa

AF:

0.321

Hom.:

6183

Bravo

AF:

0.303

TwinsUK

AF:

0.325

AC:

1205

ALSPAC

AF:

0.325

AC:

1254

ESP6500AA

AF:

0.234

AC:

1030

ESP6500EA

AF:

0.314

AC:

2697

ExAC

AF:

0.345

AC:

41913

Asia WGS

AF:

0.421

AC:

1464

AN:

3478

EpiCase

AF:

0.318

EpiControl

AF:

0.316

ClinVar

Significance: Benign

Submissions summary: Benign:18Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7Other:1

not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency, variant associated with lung cancer -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 30, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 61% of patients studied by a panel of primary immunodeficiencies. Number of patients: 58. Only high quality variants are reported. -

Microcephaly, normal intelligence and immunodeficiency

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	IntelligeneCG	Aug 18, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 28476809, 25771871, 24728327, 27153395, 12917199, 24113799, 21656575, 21166880, 22070649, 19706757, 19393077, 20143155) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Acute lymphoid leukemia

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 21, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Hereditary breast ovarian cancer syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.15

DEOGEN2

Benign

0.082

T;T;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.55

FATHMM_MKL

Benign

0.086

LIST_S2

Benign

0.084

T;T;T

MetaRNN

Benign

0.0024

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.2

N;.;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.28

PROVEAN

Benign

0.53

N;N;N

REVEL

Benign

0.10

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;.

Polyphen

0.0

B;.;.

Vest4

0.078

MPC

0.067

ClinPred

0.00096

GERP RS

3.1

Varity_R

0.059

gMVP

0.28

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over