rs864309670
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002485.5(NBN):c.742_743insGG(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 (★★). 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
NM_002485.5 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.0510
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
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 [Likely_pathogenic]. Clinvar id is 6949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.742_743insGG | p.Glu248GlyfsTer5 | frameshift_variant | 7/16 | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.742_743insGG | p.Glu248GlyfsTer5 | frameshift_variant | 7/16 | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Pathogenic:4Other:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 13, 2022 | Variant summary: NBN c.741_742dupGG (p.Glu248GlyfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. 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). The variant was absent in 251058 control chromosomes (gnomAD). c.741_742dupGG has been reported in the literature in at least one homozygous individual affected with Nijmegen Breakage Syndrome (Di Masi_2006). These data indicate that the variant may be associated with disease. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and four as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
not provided, no classification provided | literature only | GeneReviews | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2021 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6949). This premature translational stop signal has been observed in individual(s) with Nijmegen breakage syndrome (PMID: 2625251, 3802554, 16415040). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu248Glyfs*5) in the NBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Mar 01, 2006 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Nov 18, 2021 | 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); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21436738, 16415040, 22373003, 3802554, 26265251) - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 24, 2023 | The c.741_742dupGG variant, located in coding exon 7 of the NBN gene, results from a duplication of GG at nucleotide position 741, causing a translational frameshift with a predicted alternate stop codon (p.E248Gfs*5). This alteration has been reported in the homozygous state in an individual affected with a mild Nijmegen breakage syndrome phenotype (Varon R et al. Hum. Mol. Genet., 2006 Mar;15:679-89). 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). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at