NM_002485.5:c.1642A>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.1642A>G(p.Asn548Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,596 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. N548S) 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 Cov.: 32
GnomAD2 exomes AF: 0.00000398 AC: 1AN: 251214 AF XY: 0.00000736 show subpopulations
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461596Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727084 show subpopulations
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Uncertain:3
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This sequence change replaces asparagine with aspartic acid at codon 548 of the NBN protein (p.Asn548Asp). The asparagine residue is weakly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs772234785, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with NBN-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
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Hereditary cancer-predisposing syndrome Uncertain:2
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The p.N548D variant (also known as c.1642A>G), located in coding exon 11 of the NBN gene, results from an A to G substitution at nucleotide position 1642. The asparagine at codon 548 is replaced by aspartic acid, an amino acid with highly similar properties. This amino acid position is poorly 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