rs2734823

Variant names:

• chr8-89931500-A-G
• rs2734823
• ENST00000494804.2:n.7649T>C

Variant summary

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

The ENST00000494804.2(NBN):​n.7649T>C 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 0.529 in 151,972 control chromosomes in the GnomAD database, including 24,146 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 0.53 (24146 hom., cov: 32)
• Consequence: NBN ENST00000494804.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.414
• 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=-1.02).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.818 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.7649T>C		non_coding_transcript_exon_variant	Exon 15 of 15	3
NBN	ENST00000697294.1	n.*5958T>C		non_coding_transcript_exon_variant	Exon 17 of 17			ENSP00000513231.1
NBN	ENST00000697295.1	n.*5656T>C		non_coding_transcript_exon_variant	Exon 12 of 12			ENSP00000513232.1

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80319 AN: 151854 Hom.: 24074 Cov.: 32

Gnomad AFR AF: 0.825

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.509

Gnomad ASJ AF: 0.326

Gnomad EAS AF: 0.645

Gnomad SAS AF: 0.525

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.499

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

GnomAD4 genome AF: 0.529 AC: 80467 AN: 151972 Hom.: 24146 Cov.: 32 AF XY: 0.528 AC XY: 39203 AN XY: 74268

African (AFR) AF: 0.825 AC: 34214 AN: 41454

American (AMR) AF: 0.509 AC: 7772 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 1129 AN: 3468

East Asian (EAS) AF: 0.645 AC: 3334 AN: 5172

South Asian (SAS) AF: 0.528 AC: 2544 AN: 4818

European-Finnish (FIN) AF: 0.362 AC: 3815 AN: 10536

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26145 AN: 67948

Other (OTH) AF: 0.504 AC: 1065 AN: 2114

Alfa AF: 0.470 Hom.: 2443

Bravo AF: 0.550

Asia WGS AF: 0.615 AC: 2142 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.77
DANN	Benign	0.54
PhyloP100		-0.41

Splicing

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

Other links and lift over

dbSNP: rs2734823; hg19: chr8-90943728;