rs2142097

Variant names:

• chr8-89932804-T-C
• rs2142097
• ENST00000494804.2:n.6345A>G

Variant summary

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

The ENST00000494804.2(NBN):​n.6345A>G 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 0.276 in 152,070 control chromosomes in the GnomAD database, including 6,240 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 0.28 (6240 hom., cov: 32)
• Consequence: NBN ENST00000494804.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.308
• Publications: 8 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000494804.2	n.6345A>G		non_coding_transcript_exon_variant	Exon 15 of 15	3
NBN	ENST00000697294.1	n.*4654A>G		non_coding_transcript_exon_variant	Exon 17 of 17			ENSP00000513231.1
NBN	ENST00000697295.1	n.*4352A>G		non_coding_transcript_exon_variant	Exon 12 of 12			ENSP00000513232.1

Frequencies

GnomAD3 genomes AF: 0.276 AC: 41892 AN: 151952 Hom.: 6235 Cov.: 32

Gnomad AFR AF: 0.154

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.276

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.281

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

GnomAD4 genome AF: 0.276 AC: 41904 AN: 152070 Hom.: 6240 Cov.: 32 AF XY: 0.276 AC XY: 20509 AN XY: 74316

African (AFR) AF: 0.153 AC: 6356 AN: 41490

American (AMR) AF: 0.276 AC: 4216 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 882 AN: 3466

East Asian (EAS) AF: 0.405 AC: 2089 AN: 5154

South Asian (SAS) AF: 0.321 AC: 1545 AN: 4814

European-Finnish (FIN) AF: 0.306 AC: 3238 AN: 10590

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.333 AC: 22608 AN: 67966

Other (OTH) AF: 0.279 AC: 588 AN: 2110

Alfa AF: 0.307 Hom.: 8692

Bravo AF: 0.264

Asia WGS AF: 0.303 AC: 1055 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.0
DANN	Benign	0.74
PhyloP100		0.31

Splicing

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

Other links and lift over

dbSNP: rs2142097; hg19: chr8-90945032;