8-89933257-C-T

Variant names:

• chr8-89933257-C-T
• rs2021881
• ENST00000494804.2:n.5892G>A

Variant summary

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

The ENST00000494804.2(NBN):​n.5892G>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 183,692 control chromosomes in the GnomAD database, including 9,265 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 (7469 hom., cov: 33)
  • Exomes 𝑓: 0.33 (1796 hom.)
• Consequence: NBN ENST00000494804.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.305
• 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=-0.73).
• 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.*2325G>A		downstream_gene	N/A	NP_002476.2
	NBN	NM_001024688.3		c.*2325G>A		downstream_gene	N/A	NP_001019859.1
	NBN	NM_001440379.1		c.*2325G>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.5892G>A		non_coding_transcript_exon	Exon 15 of 15
	NBN	ENST00000697294.1		n.*4201G>A		non_coding_transcript_exon	Exon 17 of 17	ENSP00000513231.1
	NBN	ENST00000697295.1		n.*3899G>A		non_coding_transcript_exon	Exon 12 of 12	ENSP00000513232.1

Frequencies

GnomAD3 genomes AF: 0.313 AC: 47555 AN: 151950 Hom.: 7459 Cov.: 33

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.292

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: 0.333

Gnomad OTH AF: 0.305

GnomAD4 exome AF: 0.334 AC: 10565 AN: 31624 Hom.: 1796 AF XY: 0.333 AC XY: 4845 AN XY: 14558

African (AFR) AF: 0.283 AC: 318 AN: 1124

American (AMR) AF: 0.325 AC: 246 AN: 758

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 555 AN: 2042

East Asian (EAS) AF: 0.404 AC: 2425 AN: 5998

South Asian (SAS) AF: 0.282 AC: 71 AN: 252

European-Finnish (FIN) AF: 0.375 AC: 6 AN: 16

Middle Eastern (MID) AF: 0.242 AC: 46 AN: 190

European-Non Finnish (NFE) AF: 0.327 AC: 6114 AN: 18682

Other (OTH) AF: 0.306 AC: 784 AN: 2562

GnomAD4 genome AF: 0.313 AC: 47593 AN: 152068 Hom.: 7469 Cov.: 33 AF XY: 0.312 AC XY: 23213 AN XY: 74334

African (AFR) AF: 0.281 AC: 11662 AN: 41478

American (AMR) AF: 0.292 AC: 4457 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 904 AN: 3466

East Asian (EAS) AF: 0.407 AC: 2103 AN: 5172

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

European-Finnish (FIN) AF: 0.307 AC: 3238 AN: 10546

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

European-Non Finnish (NFE) AF: 0.333 AC: 22653 AN: 67990

Other (OTH) AF: 0.303 AC: 639 AN: 2112

Alfa AF: 0.326 Hom.: 2162

Bravo AF: 0.307

Asia WGS AF: 0.308 AC: 1074 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		0.30

Splicing

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

Other links and lift over

dbSNP: rs2021881; hg19: chr8-90945485;