NM_002485.5:c.2184+228A>C

Variant names:

• chr8-89943025-T-G
• rs6470524
• NM_002485.5:c.2184+228A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002485.5(NBN):​c.2184+228A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.305 in 150,110 control chromosomes in the GnomAD database, including 7,201 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.31 (7201 hom., cov: 30)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.750
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 8-89943025-T-G is Benign according to our data. Variant chr8-89943025-T-G is described in ClinVar as Benign. ClinVar VariationId is 1222104.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.431 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.2184+228A>C		intron	N/A	NP_002476.2
	NBN	NM_001024688.3		c.1938+228A>C		intron	N/A	NP_001019859.1
	NBN	NM_001440379.1		c.1938+228A>C		intron	N/A	NP_001427308.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.2184+228A>C		intron	N/A	ENSP00000265433.4
	NBN	ENST00000697311.1		n.*213A>C		non_coding_transcript_exon	Exon 14 of 16	ENSP00000513246.1
	NBN	ENST00000697311.1		n.*213A>C		3_prime_UTR	Exon 14 of 16	ENSP00000513246.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 45775 AN: 150008 Hom.: 7197 Cov.: 30

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.262

Gnomad AMR AF: 0.338

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.448

Gnomad SAS AF: 0.433

Gnomad FIN AF: 0.330

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.320

Gnomad OTH AF: 0.316

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

GnomAD4 genome AF: 0.305 AC: 45793 AN: 150110 Hom.: 7201 Cov.: 30 AF XY: 0.310 AC XY: 22648 AN XY: 73172

African (AFR) AF: 0.229 AC: 9324 AN: 40746

American (AMR) AF: 0.338 AC: 5124 AN: 15144

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1065 AN: 3466

East Asian (EAS) AF: 0.447 AC: 2287 AN: 5122

South Asian (SAS) AF: 0.434 AC: 2074 AN: 4774

European-Finnish (FIN) AF: 0.330 AC: 3266 AN: 9886

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.320 AC: 21664 AN: 67686

Other (OTH) AF: 0.320 AC: 669 AN: 2090

Alfa AF: 0.315 Hom.: 1016

Bravo AF: 0.300

Asia WGS AF: 0.417 AC: 1447 AN: 3468

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.3
DANN	Benign	0.70
PhyloP100		-0.75
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: rs6470524; hg19: chr8-90955253;