NM_002485.5:c.1877T>G
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_002485.5(NBN):c.1877T>G(p.Leu626Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000019 in 1,581,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L626F) has been classified as Uncertain significance.
Frequency
Consequence
NM_002485.5 missense
Scores
Clinical Significance
Conservation
Publications
- Nijmegen breakage syndromeInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health
- rhabdomyosarcomaInheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
- idiopathic aplastic anemiaInheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
- prostate cancerInheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
- hereditary breast carcinomaInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 0 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome AF: 0.00000140 AC: 2AN: 1429784Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0AN XY: 711684 show subpopulations
Age Distribution
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152148Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74324 show subpopulations
ClinVar
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Uncertain:2
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This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 626 of the NBN protein (p.Leu626Arg). 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: 530716). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Hereditary cancer-predisposing syndrome Uncertain:1
The p.L626R variant (also known as c.1877T>G), located in coding exon 12 of the NBN gene, results from a T to G substitution at nucleotide position 1877. The leucine at codon 626 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at