rs1235369

Variant names:

• chr8-89961510-A-G
• rs1235369
• NM_002485.5:c.995-2656T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_002485.5(NBN):​c.995-2656T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 152,296 control chromosomes in the GnomAD database, including 62 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 0.027 (62 hom., cov: 32)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.376
• 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=-0.83).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0269 (4096/152296) while in subpopulation NFE AF = 0.039 (2653/68024). AF 95% confidence interval is 0.0378. There are 62 homozygotes in GnomAd4. There are 1981 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 62 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.995-2656T>C		intron_variant	Intron 8 of 15	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.995-2656T>C		intron_variant	Intron 8 of 15	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.0269 AC: 4096 AN: 152178 Hom.: 63 Cov.: 32

Gnomad AFR AF: 0.00688

Gnomad AMI AF: 0.0439

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.0268

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00911

Gnomad FIN AF: 0.0528

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0390

Gnomad OTH AF: 0.0273

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

GnomAD4 genome AF: 0.0269 AC: 4096 AN: 152296 Hom.: 62 Cov.: 32 AF XY: 0.0266 AC XY: 1981 AN XY: 74484

African (AFR) AF: 0.00688 AC: 286 AN: 41570

American (AMR) AF: 0.0233 AC: 356 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0268 AC: 93 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00911 AC: 44 AN: 4828

European-Finnish (FIN) AF: 0.0528 AC: 560 AN: 10610

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0390 AC: 2653 AN: 68024

Other (OTH) AF: 0.0270 AC: 57 AN: 2110

Alfa AF: 0.0236 Hom.: 23

Bravo AF: 0.0241

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.2
DANN	Benign	0.76
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism

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: rs1235369; hg19: chr8-90973738;