chr8-89943291-T-C
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2
The NM_002485.5(NBN):āc.2146A>Gā(p.Asn716Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00145 in 1,613,746 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ). Synonymous variant affecting the same amino acid position (i.e. N716N) has been classified as Likely benign.
Frequency
Consequence
NM_002485.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.2146A>G | p.Asn716Asp | missense_variant | 14/16 | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.2146A>G | p.Asn716Asp | missense_variant | 14/16 | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00760 AC: 1157AN: 152162Hom.: 17 Cov.: 32
GnomAD3 exomes AF: 0.00196 AC: 493AN: 251350Hom.: 7 AF XY: 0.00150 AC XY: 204AN XY: 135840
GnomAD4 exome AF: 0.000801 AC: 1170AN: 1461466Hom.: 17 Cov.: 31 AF XY: 0.000707 AC XY: 514AN XY: 727048
GnomAD4 genome AF: 0.00764 AC: 1164AN: 152280Hom.: 17 Cov.: 32 AF XY: 0.00724 AC XY: 539AN XY: 74488
ClinVar
Submissions by phenotype
not specified Benign:5Other:1
Benign, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 19, 2015 | - - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The NBN p.Asn716Asp variant was identified in 1 of 164 proband chromosomes (frequency: 0.006) from individuals or families with cancer and was present in 5 of 1362 control chromosomes (frequency: 0.004) from healthy individuals (Wang 2013, Bodian 2014). The variant was also identified in the following databases: dbSNP (ID: rs72563785) as "With other allele", ClinVar (5x benign, 1x uncertain significance), Clinvitae, and Zhejiang Colon Cancer Database. The variant was not identified in the Cosmic or LOVD 3.0 databases. The variant was identified in control databases in 716 of 277088 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 651 of 24032 chromosomes (freq: 0.03). The p.Asn716 residue is conserved in mammals but not in more distantly related organisms. However four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 27, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jun 25, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 23, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Microcephaly, normal intelligence and immunodeficiency Benign:3
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 31, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Hereditary cancer-predisposing syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Vantari Genetics | Feb 04, 2016 | - - |
Likely benign, no assertion criteria provided | clinical testing | True Health Diagnostics | Sep 11, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 28, 2014 | This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:2
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jan 06, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 02, 2016 | Variant summary: The c.2146A>G variant affects a conserved nucleotide, resulting in amino acid change from Asn to Asp. 3/4 in-silico tools predict this variant to be benign. This variant is found in 295/121388 control chromosomes (including 5 homozygotes) at a frequency of 0.0024302. It was predominantly observed in the African subpopulation at a frequency of 2.7% including 5 homozygous occurrences. This frequency significantly exceeds the maximal expected allele frequency for a pathogenic variant in NBN (0.25%), suggesting this is a benign polymorphism found primarily in population(s) of African origin. In addition, multiple clinical laboratories have classified this variant as benign/likely benign. One internal sample with this variant also carried a deleterious variant PMS2 c.2186_2187delTC, supporting bening outcome. Taken together, this variant has been classified as Benign. - |
Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | May 25, 2022 | - - |
Hereditary breast ovarian cancer syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Apr 19, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at