chr8-89980442-G-C

Variant names:

• chr8-89980442-G-C
• rs1805841
• NM_002485.5:c.480+292C>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002485.5(NBN):​c.480+292C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 151,482 control chromosomes in the GnomAD database, including 21,876 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.51 (21876 hom., cov: 29)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.644
• Publications: 6 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 8-89980442-G-C is Benign according to our data. Variant chr8-89980442-G-C is described in ClinVar as Benign. ClinVar VariationId is 1230696.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.761 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.480+292C>G		intron_variant	Intron 4 of 15	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.480+292C>G		intron_variant	Intron 4 of 15	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.508 AC: 76824 AN: 151364 Hom.: 21807 Cov.: 29

Gnomad AFR AF: 0.767

Gnomad AMI AF: 0.311

Gnomad AMR AF: 0.521

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.649

Gnomad SAS AF: 0.521

Gnomad FIN AF: 0.436

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.358

Gnomad OTH AF: 0.489

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

GnomAD4 genome AF: 0.508 AC: 76963 AN: 151482 Hom.: 21876 Cov.: 29 AF XY: 0.514 AC XY: 38055 AN XY: 73990

African (AFR) AF: 0.768 AC: 31699 AN: 41284

American (AMR) AF: 0.521 AC: 7928 AN: 15214

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1201 AN: 3458

East Asian (EAS) AF: 0.648 AC: 3329 AN: 5136

South Asian (SAS) AF: 0.523 AC: 2502 AN: 4782

European-Finnish (FIN) AF: 0.436 AC: 4571 AN: 10480

Middle Eastern (MID) AF: 0.347 AC: 102 AN: 294

European-Non Finnish (NFE) AF: 0.358 AC: 24313 AN: 67826

Other (OTH) AF: 0.493 AC: 1035 AN: 2098

Alfa AF: 0.269 Hom.: 589

Bravo AF: 0.524

Asia WGS AF: 0.622 AC: 2161 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 09, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.98
DANN	Benign	0.66
PhyloP100		-0.64
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1805841; hg19: chr8-90992670;