Genetic Variant NBN:c.2184+123G>A (chr8-89943130-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

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

The NM_002485.5(NBN):c.2184+123G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 928,244 control chromosomes in the GnomAD database, including 55,784 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8324 hom., cov: 30)

Exomes 𝑓: 0.35 ( 47460 hom. )

Consequence

NBN
NM_002485.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.155

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

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

BP6

Variant 8-89943130-C-T is Benign according to our data. Variant chr8-89943130-C-T is described in ClinVar as [Benign]. Clinvar id is 1177037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.2184+123G>A		intron_variant	Intron 14 of 15	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.2184+123G>A		intron_variant	Intron 14 of 15	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.333

AC:

50003

AN:

150016

Hom.:

8315

Cov.:

show subpopulations

Gnomad AFR

AF:

0.315

Gnomad AMI

AF:

0.264

Gnomad AMR

AF:

0.352

Gnomad ASJ

AF:

0.315

Gnomad EAS

AF:

0.452

Gnomad SAS

AF:

0.437

Gnomad FIN

AF:

0.356

Gnomad MID

AF:

0.287

Gnomad NFE

AF:

0.322

Gnomad OTH

AF:

0.337

GnomAD4 exome

AF:

0.345

AC:

268767

AN:

778118

Hom.:

47460

AF XY:

0.349

AC XY:

142737

AN XY:

409236

show subpopulations

Gnomad4 AFR exome

AF:

0.314

Gnomad4 AMR exome

AF:

0.361

Gnomad4 ASJ exome

AF:

0.319

Gnomad4 EAS exome

AF:

0.485

Gnomad4 SAS exome

AF:

0.429

Gnomad4 FIN exome

AF:

0.362

Gnomad4 NFE exome

AF:

0.325

Gnomad4 OTH exome

AF:

0.349

GnomAD4 genome

AF:

0.333

AC:

50037

AN:

150126

Hom.:

8324

Cov.:

AF XY:

0.338

AC XY:

24786

AN XY:

73306

show subpopulations

Gnomad4 AFR

AF:

0.315

Gnomad4 AMR

AF:

0.352

Gnomad4 ASJ

AF:

0.315

Gnomad4 EAS

AF:

0.451

Gnomad4 SAS

AF:

0.438

Gnomad4 FIN

AF:

0.356

Gnomad4 NFE

AF:

0.322

Gnomad4 OTH

AF:

0.341

Alfa

AF:

0.156

Hom.:

306

Bravo

AF:

0.326

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephaly, normal intelligence and immunodeficiency

Benign:1

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

2.0

DANN

Benign

0.21

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