rs786201965
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Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_002485.5(NBN):c.2071-1G>C variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000138 in 1,448,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
NBN
NM_002485.5 splice_acceptor
NM_002485.5 splice_acceptor
Scores
5
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.17
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 16 ACMG points.
PVS1
Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.049889624 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 8-89943367-C-G is Pathogenic according to our data. Variant chr8-89943367-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 185152.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.2071-1G>C | splice_acceptor_variant | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.2071-1G>C | splice_acceptor_variant | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
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32
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1448480Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 721460
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GnomAD4 genome Cov.: 32
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32
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Pathogenic:3
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 31, 2020 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 29, 2023 | This sequence change affects an acceptor splice site in intron 13 of the NBN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 185152). Studies have shown that disruption of this splice site results in skipping of exon 14, but is expected to preserve the integrity of the reading-frame (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 18, 2016 | - - |
not provided Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | NBN: PVS1:Strong, PM2 - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2017 | This pathogenic variant is denoted NBN c.2071-1G>C or IVS13-1G>C and consists of a G>C nucleotide substitution at the -1 position of intron 13 of the NBN gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. This variant has not, to our knowledge, been published in the literature. - |
Aplastic anemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 20, 2023 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 28, 2023 | The c.2071-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 14 of the NBN gene. This alteration was identified in an individual who underwent hereditary cancer multi-gene panel testing (LaDuca H et al. PLoS ONE, 2017 Feb;12:e0170843). This alteration was also observed in 0/3,236 cases with invasive epithelial ovarian cancer and 1/3,431 controls (Ramus SJ et al. J. Natl. Cancer Inst., 2015 Nov;107). This variant was also reported in 2/60,466 breast cancer cases and in 3/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
D;D
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: -1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at