8-89933286-C-T

Variant names:

• chr8-89933286-C-T
• rs2021882
• ENST00000494804.2:n.5863G>A

Variant summary

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

The ENST00000494804.2(NBN):​n.5863G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 189,600 control chromosomes in the GnomAD database, including 9,562 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 0.31 (7450 hom., cov: 32)
  • Exomes 𝑓: 0.33 (2112 hom.)
• Consequence: NBN ENST00000494804.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.627
• Publications: 4 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000494804.2. 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.*2296G>A		downstream_gene	N/A	NP_002476.2
	NBN	NM_001024688.3		c.*2296G>A		downstream_gene	N/A	NP_001019859.1
	NBN	NM_001440379.1		c.*2296G>A		downstream_gene	N/A	NP_001427308.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000494804.2	TSL:3	n.5863G>A		non_coding_transcript_exon	Exon 15 of 15
	NBN	ENST00000697294.1		n.*4172G>A		non_coding_transcript_exon	Exon 17 of 17	ENSP00000513231.1
	NBN	ENST00000697295.1		n.*3870G>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000513232.1

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47464 AN: 151908 Hom.: 7440 Cov.: 32

Gnomad AFR AF: 0.282

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.291

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.304

GnomAD4 exome AF: 0.334 AC: 12563 AN: 37574 Hom.: 2112 Cov.: 0 AF XY: 0.333 AC XY: 5789 AN XY: 17376

African (AFR) AF: 0.287 AC: 406 AN: 1416

American (AMR) AF: 0.333 AC: 320 AN: 960

Ashkenazi Jewish (ASJ) AF: 0.273 AC: 667 AN: 2446

East Asian (EAS) AF: 0.404 AC: 2648 AN: 6562

South Asian (SAS) AF: 0.296 AC: 93 AN: 314

European-Finnish (FIN) AF: 0.292 AC: 7 AN: 24

Middle Eastern (MID) AF: 0.235 AC: 54 AN: 230

European-Non Finnish (NFE) AF: 0.329 AC: 7393 AN: 22502

Other (OTH) AF: 0.313 AC: 975 AN: 3120

GnomAD4 genome AF: 0.312 AC: 47502 AN: 152026 Hom.: 7450 Cov.: 32 AF XY: 0.312 AC XY: 23169 AN XY: 74292

African (AFR) AF: 0.281 AC: 11671 AN: 41470

American (AMR) AF: 0.291 AC: 4443 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 905 AN: 3466

East Asian (EAS) AF: 0.406 AC: 2104 AN: 5180

South Asian (SAS) AF: 0.321 AC: 1547 AN: 4822

European-Finnish (FIN) AF: 0.307 AC: 3239 AN: 10534

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22566 AN: 67980

Other (OTH) AF: 0.302 AC: 637 AN: 2110

Alfa AF: 0.326 Hom.: 1063

Bravo AF: 0.306

Asia WGS AF: 0.307 AC: 1071 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	10
DANN	Benign	0.67
PhyloP100		-0.63

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2021882; hg19: chr8-90945514;