NM_002485.5:c.2184+1000T>C

Variant names:

• chr8-89942253-A-G
• rs6470522
• NM_002485.5:c.2184+1000T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002485.5(NBN):​c.2184+1000T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.86 in 152,164 control chromosomes in the GnomAD database, including 56,656 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.86 (56656 hom., cov: 32)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.309
• Publications: 18 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Orphanet, ClinGen
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.941 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.2184+1000T>C		intron	N/A	NP_002476.2
	NBN	NM_001024688.3		c.1938+1000T>C		intron	N/A	NP_001019859.1	A0A0C4DG07
	NBN	NM_001440379.1		c.1938+1000T>C		intron	N/A	NP_001427308.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.2184+1000T>C		intron	N/A	ENSP00000265433.4	O60934
	NBN	ENST00000697309.1		c.2184+1000T>C		intron	N/A	ENSP00000513244.1	A0A8V8TKY5
	NBN	ENST00000697293.1		c.2235+536T>C		intron	N/A	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes AF: 0.860 AC: 130762 AN: 152046 Hom.: 56592 Cov.: 32

Gnomad AFR AF: 0.949

Gnomad AMI AF: 0.708

Gnomad AMR AF: 0.832

Gnomad ASJ AF: 0.828

Gnomad EAS AF: 0.670

Gnomad SAS AF: 0.827

Gnomad FIN AF: 0.821

Gnomad MID AF: 0.869

Gnomad NFE AF: 0.839

Gnomad OTH AF: 0.854

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

GnomAD4 genome AF: 0.860 AC: 130883 AN: 152164 Hom.: 56656 Cov.: 32 AF XY: 0.858 AC XY: 63810 AN XY: 74368

African (AFR) AF: 0.949 AC: 39435 AN: 41552

American (AMR) AF: 0.833 AC: 12726 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.828 AC: 2876 AN: 3472

East Asian (EAS) AF: 0.669 AC: 3462 AN: 5174

South Asian (SAS) AF: 0.827 AC: 3992 AN: 4826

European-Finnish (FIN) AF: 0.821 AC: 8681 AN: 10580

Middle Eastern (MID) AF: 0.863 AC: 252 AN: 292

European-Non Finnish (NFE) AF: 0.839 AC: 57009 AN: 67966

Other (OTH) AF: 0.855 AC: 1804 AN: 2110

Alfa AF: 0.842 Hom.: 226586

Bravo AF: 0.863

Asia WGS AF: 0.774 AC: 2690 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.1
DANN	Benign	0.70
PhyloP100		0.31
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: rs6470522; hg19: chr8-90954481;