8-89966609-C-T

Variant names:

• chr8-89966609-C-T
• rs7006322
• NM_002485.5:c.897-2102G>A

Variant summary

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

The NM_002485.5(NBN):​c.897-2102G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.334 in 152,002 control chromosomes in the GnomAD database, including 8,509 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 0.33 (8509 hom., cov: 32)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.359
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.436 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.897-2102G>A		intron	N/A	NP_002476.2
	NBN	NM_001024688.3		c.651-2102G>A		intron	N/A	NP_001019859.1
	NBN	NM_001440379.1		c.651-2102G>A		intron	N/A	NP_001427308.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.897-2102G>A		intron	N/A	ENSP00000265433.4
	NBN	ENST00000697309.1		c.897-2102G>A		intron	N/A	ENSP00000513244.1
	NBN	ENST00000697293.1		c.897-2102G>A		intron	N/A	ENSP00000513230.1

Frequencies

GnomAD3 genomes AF: 0.334 AC: 50668 AN: 151884 Hom.: 8499 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.267

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.342

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

GnomAD4 genome AF: 0.334 AC: 50714 AN: 152002 Hom.: 8509 Cov.: 32 AF XY: 0.339 AC XY: 25149 AN XY: 74278

African (AFR) AF: 0.317 AC: 13147 AN: 41486

American (AMR) AF: 0.353 AC: 5387 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1092 AN: 3468

East Asian (EAS) AF: 0.451 AC: 2330 AN: 5166

South Asian (SAS) AF: 0.437 AC: 2105 AN: 4818

European-Finnish (FIN) AF: 0.353 AC: 3716 AN: 10530

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21877 AN: 67946

Other (OTH) AF: 0.347 AC: 732 AN: 2110

Alfa AF: 0.335 Hom.: 1136

Bravo AF: 0.330

Asia WGS AF: 0.424 AC: 1469 AN: 3462

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.95
DANN	Benign	0.45
PhyloP100		-0.36
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: rs7006322; hg19: chr8-90978837;