chr8-89970517-T-TCC

Variant names:

• chr8-89970517-T-TCC
• rs864309670
• NM_002485.5:c.741_742dupGG

Variant summary

Our verdict is Pathogenic. The variant received 22 ACMG points: 22P and 0B. PVS1 PS3 PM2 PP5_Very_Strong

The NM_002485.5(NBN):​c.741_742dupGG​(p.Glu248GlyfsTer5) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002555848: Experimental evidence has shown that this variant affects mRNA splicing: recovered transcripts from a homozygous patient were missing exons 6-7 (Varon_2006). Complementation experiments using mouse cells deficient in NBN showed that this alternative transcript was able to rescue some cell survival (Varon_2006)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E248E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NBN NM_002485.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: -0.0510
• 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: 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: Pathogenic. The variant received 22 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002555848: Experimental evidence has shown that this variant affects mRNA splicing: recovered transcripts from a homozygous patient were missing exons 6-7 (Varon_2006). Complementation experiments using mouse cells deficient in NBN showed that this alternative transcript was able to rescue some cell survival (Varon_2006).; SCV000778964: Published functional studies demonstrate a damaging effect showing an alternatively spliced transcript involving an in-frame deletion of exon 6 and 7 and also the absence of full length NBN protein by immunoprecipitation (Varon 2006, Salewsky 2016); SCV002671615: Functional studies have shown that this variant produces an abnormal in frame transcript lacking exons 6 and 7 that can produce a protein with partial functionality (Varon R et al. Hum. Mol. Genet., 2006 Mar;15:679-89).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-89970517-T-TCC is Pathogenic according to our data. Variant chr8-89970517-T-TCC is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.741_742dupGG	p.Glu248GlyfsTer5	frameshift	Exon 7 of 16	NP_002476.2
	NBN	NM_001024688.3		c.495_496dupGG	p.Glu166GlyfsTer5	frameshift	Exon 8 of 17	NP_001019859.1	A0A0C4DG07
	NBN	NM_001440379.1		c.495_496dupGG	p.Glu166GlyfsTer5	frameshift	Exon 7 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.741_742dupGG	p.Glu248GlyfsTer5	frameshift	Exon 7 of 16	ENSP00000265433.4	O60934
	NBN	ENST00000697309.1		c.741_742dupGG	p.Glu248GlyfsTer5	frameshift	Exon 7 of 15	ENSP00000513244.1	A0A8V8TKY5
	NBN	ENST00000697293.1		c.741_742dupGG	p.Glu248GlyfsTer5	frameshift	Exon 7 of 17	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Microcephaly, normal intelligence and immunodeficiency (5)
1	-	-	Hereditary cancer-predisposing syndrome (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.051
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs864309670; hg19: chr8-90982745;