rs6998169

Variant names:

• chr8-89938033-T-A
• rs6998169
• NM_002485.5:c.2185-958A>T

Your query was ambiguous. Multiple possible variants found:

• chr8-89938033-T-A
• chr8-89938033-T-G

Variant summary

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

The NM_002485.5(NBN):​c.2185-958A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0741 in 152,256 control chromosomes in the GnomAD database, including 557 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 0.074 (557 hom., cov: 32)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.375
• 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=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.124 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.2185-958A>T		intron_variant	Intron 14 of 15	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.2185-958A>T		intron_variant	Intron 14 of 15	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.0741 AC: 11274 AN: 152138 Hom.: 555 Cov.: 32

Gnomad AFR AF: 0.0182

Gnomad AMI AF: 0.0648

Gnomad AMR AF: 0.0596

Gnomad ASJ AF: 0.153

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.131

Gnomad FIN AF: 0.0891

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.106

Gnomad OTH AF: 0.0847

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

GnomAD4 genome AF: 0.0741 AC: 11285 AN: 152256 Hom.: 557 Cov.: 32 AF XY: 0.0739 AC XY: 5502 AN XY: 74448

African (AFR) AF: 0.0182 AC: 756 AN: 41570

American (AMR) AF: 0.0595 AC: 910 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.153 AC: 531 AN: 3472

East Asian (EAS) AF: 0.00231 AC: 12 AN: 5188

South Asian (SAS) AF: 0.133 AC: 641 AN: 4820

European-Finnish (FIN) AF: 0.0891 AC: 945 AN: 10608

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.106 AC: 7205 AN: 67990

Other (OTH) AF: 0.0843 AC: 178 AN: 2112

Alfa AF: 0.0948 Hom.: 93

Bravo AF: 0.0670

Asia WGS AF: 0.0540 AC: 188 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	12
DANN	Benign	0.88
PhyloP100		0.38
Mutation Taster		=100/0	polymorphism (auto)

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: rs6998169; hg19: chr8-90950261;