rs7840099

Variant names:

• chr8-89943130-C-T
• rs7840099
• NM_002485.5:c.2184+123G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-89943130-C-T
• chr8-89943130-C-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002485.5(NBN):​c.2184+123G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.343 in 928,244 control chromosomes in the GnomAD database, including 55,784 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8324 hom., cov: 30)
  • Exomes 𝑓: 0.35 (47460 hom.)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.155
• Publications: 12 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Orphanet, ClinGen
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 8-89943130-C-T is Benign according to our data. Variant chr8-89943130-C-T is described in ClinVar as Benign. ClinVar VariationId is 1177037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002485.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.2184+123G>A		intron	N/A	NP_002476.2
	NBN	NM_001024688.3		c.1938+123G>A		intron	N/A	NP_001019859.1	A0A0C4DG07
	NBN	NM_001440379.1		c.1938+123G>A		intron	N/A	NP_001427308.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.2184+123G>A		intron	N/A	ENSP00000265433.4	O60934
	NBN	ENST00000697309.1		c.2184+123G>A		intron	N/A	ENSP00000513244.1	A0A8V8TKY5
	NBN	ENST00000697293.1		c.2184+123G>A		intron	N/A	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes AF: 0.333 AC: 50003 AN: 150016 Hom.: 8315 Cov.: 30

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.356

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.337

GnomAD4 exome AF: 0.345 AC: 268767 AN: 778118 Hom.: 47460 AF XY: 0.349 AC XY: 142737 AN XY: 409236

African (AFR) AF: 0.314 AC: 6121 AN: 19464

American (AMR) AF: 0.361 AC: 13432 AN: 37232

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 6728 AN: 21070

East Asian (EAS) AF: 0.485 AC: 16502 AN: 34026

South Asian (SAS) AF: 0.429 AC: 29616 AN: 68976

European-Finnish (FIN) AF: 0.362 AC: 14822 AN: 40946

Middle Eastern (MID) AF: 0.340 AC: 1507 AN: 4438

European-Non Finnish (NFE) AF: 0.325 AC: 166974 AN: 514500

Other (OTH) AF: 0.349 AC: 13065 AN: 37466

GnomAD4 genome AF: 0.333 AC: 50037 AN: 150126 Hom.: 8324 Cov.: 30 AF XY: 0.338 AC XY: 24786 AN XY: 73306

African (AFR) AF: 0.315 AC: 12642 AN: 40146

American (AMR) AF: 0.352 AC: 5324 AN: 15126

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1091 AN: 3462

East Asian (EAS) AF: 0.451 AC: 2308 AN: 5118

South Asian (SAS) AF: 0.438 AC: 2100 AN: 4794

European-Finnish (FIN) AF: 0.356 AC: 3686 AN: 10360

Middle Eastern (MID) AF: 0.295 AC: 86 AN: 292

European-Non Finnish (NFE) AF: 0.322 AC: 21855 AN: 67854

Other (OTH) AF: 0.341 AC: 707 AN: 2072

Alfa AF: 0.166 Hom.: 343

Bravo AF: 0.326

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Microcephaly, normal intelligence and immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.0
DANN	Benign	0.21
PhyloP100		0.15
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: rs7840099; hg19: chr8-90955358; COSMIC: COSV55372468; COSMIC: COSV55372468;