rs2735388

Variant names:

• chr8-89939069-T-A
• rs2735388
• NM_002485.5:c.2185-1994A>T

Your query was ambiguous. Multiple possible variants found:

• chr8-89939069-T-A
• chr8-89939069-T-C
• chr8-89939069-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.2185-1994A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 152,004 control chromosomes in the GnomAD database, including 13,161 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 0.40 (13161 hom., cov: 32)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.582
• Publications: 4 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=-0.74).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.594 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.2185-1994A>T		intron	N/A	NP_002476.2
	NBN	NM_001024688.3		c.1939-1994A>T		intron	N/A	NP_001019859.1
	NBN	NM_001440379.1		c.1939-1994A>T		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.2185-1994A>T		intron	N/A	ENSP00000265433.4
	NBN	ENST00000474821.2	TSL:2	n.1611A>T		non_coding_transcript_exon	Exon 1 of 2
	NBN	ENST00000697309.1		c.2185-3457A>T		intron	N/A	ENSP00000513244.1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60238 AN: 151886 Hom.: 13124 Cov.: 32

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.322

Gnomad ASJ AF: 0.262

Gnomad EAS AF: 0.410

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.298

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.318

Gnomad OTH AF: 0.367

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

GnomAD4 genome AF: 0.397 AC: 60334 AN: 152004 Hom.: 13161 Cov.: 32 AF XY: 0.394 AC XY: 29284 AN XY: 74302

African (AFR) AF: 0.600 AC: 24880 AN: 41456

American (AMR) AF: 0.322 AC: 4919 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.262 AC: 910 AN: 3468

East Asian (EAS) AF: 0.409 AC: 2113 AN: 5170

South Asian (SAS) AF: 0.335 AC: 1611 AN: 4810

European-Finnish (FIN) AF: 0.298 AC: 3142 AN: 10554

Middle Eastern (MID) AF: 0.272 AC: 80 AN: 294

European-Non Finnish (NFE) AF: 0.318 AC: 21613 AN: 67972

Other (OTH) AF: 0.365 AC: 768 AN: 2106

Alfa AF: 0.206 Hom.: 390

Bravo AF: 0.404

Asia WGS AF: 0.359 AC: 1248 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.7
DANN	Benign	0.88
PhyloP100		-0.58
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: rs2735388; hg19: chr8-90951297;