8-89946194-T-C

Variant names:

• chr8-89946194-T-C
• rs1061302
• NM_002485.5:c.2016A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002485.5(NBN):​c.2016A>G​(p.Pro672Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.329 in 1,596,714 control chromosomes in the GnomAD database, including 88,581 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P672P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.31 (7460 hom., cov: 32)
  • Exomes 𝑓: 0.33 (81121 hom.)
• Consequence: NBN NM_002485.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -2.58
• Publications: 59 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 8-89946194-T-C is Benign according to our data. Variant chr8-89946194-T-C is described in ClinVar as Benign. ClinVar VariationId is 183696.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.58 with no splicing effect.
• 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.2016A>G	p.Pro672Pro	synonymous	Exon 13 of 16	NP_002476.2
	NBN	NM_001024688.3		c.1770A>G	p.Pro590Pro	synonymous	Exon 14 of 17	NP_001019859.1	A0A0C4DG07
	NBN	NM_001440379.1		c.1770A>G	p.Pro590Pro	synonymous	Exon 13 of 16	NP_001427308.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.2016A>G	p.Pro672Pro	synonymous	Exon 13 of 16	ENSP00000265433.4	O60934
	NBN	ENST00000697309.1		c.2016A>G	p.Pro672Pro	synonymous	Exon 13 of 15	ENSP00000513244.1	A0A8V8TKY5
	NBN	ENST00000697293.1		c.2016A>G	p.Pro672Pro	synonymous	Exon 13 of 17	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46788 AN: 151810 Hom.: 7452 Cov.: 32

Gnomad AFR AF: 0.230

Gnomad AMI AF: 0.265

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.307

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.352

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.321

GnomAD2 exomes AF: 0.347 AC: 87004 AN: 250934 AF XY: 0.351

Gnomad AFR exome AF: 0.230

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.316

Gnomad EAS exome AF: 0.456

Gnomad FIN exome AF: 0.355

Gnomad NFE exome AF: 0.325

Gnomad OTH exome AF: 0.332

GnomAD4 exome AF: 0.331 AC: 478330 AN: 1444786 Hom.: 81121 Cov.: 32 AF XY: 0.334 AC XY: 240316 AN XY: 719804

African (AFR) AF: 0.228 AC: 7556 AN: 33162

American (AMR) AF: 0.353 AC: 15776 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.312 AC: 8114 AN: 26012

East Asian (EAS) AF: 0.479 AC: 18875 AN: 39408

South Asian (SAS) AF: 0.428 AC: 36721 AN: 85808

European-Finnish (FIN) AF: 0.362 AC: 19256 AN: 53218

Middle Eastern (MID) AF: 0.337 AC: 1908 AN: 5666

European-Non Finnish (NFE) AF: 0.319 AC: 350041 AN: 1097036

Other (OTH) AF: 0.336 AC: 20083 AN: 59796

GnomAD4 genome AF: 0.308 AC: 46816 AN: 151928 Hom.: 7460 Cov.: 32 AF XY: 0.314 AC XY: 23276 AN XY: 74238

African (AFR) AF: 0.230 AC: 9541 AN: 41466

American (AMR) AF: 0.341 AC: 5214 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.307 AC: 1067 AN: 3470

East Asian (EAS) AF: 0.451 AC: 2326 AN: 5152

South Asian (SAS) AF: 0.438 AC: 2110 AN: 4822

European-Finnish (FIN) AF: 0.352 AC: 3723 AN: 10564

Middle Eastern (MID) AF: 0.277 AC: 81 AN: 292

European-Non Finnish (NFE) AF: 0.322 AC: 21829 AN: 67882

Other (OTH) AF: 0.325 AC: 684 AN: 2102

Alfa AF: 0.310 Hom.: 13879

Bravo AF: 0.300

Asia WGS AF: 0.421 AC: 1463 AN: 3472

EpiCase AF: 0.318

EpiControl AF: 0.317

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Microcephaly, normal intelligence and immunodeficiency (5)
-	-	3	not provided (3)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	Acute lymphoid leukemia (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.47
DANN	Benign	0.43
PhyloP100		-2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1061302; hg19: chr8-90958422; COSMIC: COSV55371426;