rs750349053
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2
The NM_144573.4(NEXN):c.836G>A(p.Arg279His) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R279C) has been classified as Likely benign.
Frequency
Consequence
NM_144573.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEXN | NM_144573.4 | c.836G>A | p.Arg279His | missense_variant | 8/13 | ENST00000334785.12 | NP_653174.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEXN | ENST00000334785.12 | c.836G>A | p.Arg279His | missense_variant | 8/13 | 1 | NM_144573.4 | ENSP00000333938.7 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152054Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000201 AC: 5AN: 248420Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 134974
GnomAD4 exome AF: 0.0000151 AC: 22AN: 1461544Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 10AN XY: 727074
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152054Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74266
ClinVar
Submissions by phenotype
Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 22, 2021 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 07, 2023 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 279 of the NEXN protein (p.Arg279His). This variant is present in population databases (rs750349053, gnomAD 0.009%). This missense change has been observed in individual(s) with sudden unexplained death (PMID: 29247119). ClinVar contains an entry for this variant (Variation ID: 229059). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NEXN protein function with a negative predictive value of 80%. 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. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 12, 2015 | The p.Arg279His variant in NEXN has not been previously reported in individuals with cardiomyopathy, but has been identified in 1/65886 of European chromosomes and 1/11492 of Latino chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org). Computational prediction tools and conservation an alysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Arg279His variant is uncertain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 08, 2023 | The NEXN c.836G>A; p.Arg279His variant (rs750349053) is reported in the literature in a cohort of individuals with sudden unexpected death, although its clinical significance was not demonstrated (Lin 2017). This variant is found in the general population with a low overall allele frequency of 0.002% (5/248,420 alleles) in the Genome Aggregation Database. Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.174). Given the lack of clinical and functional data, the significance of the p.Arg279His variant is uncertain at this time. References: Lin Y et al. Applying High-Resolution Variant Classification to Cardiac Arrhythmogenic Gene Testing in a Demographically Diverse Cohort of Sudden Unexplained Deaths. Circ Cardiovasc Genet. 2017 Dec;10(6):e001839. PMID: 29247119. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 05, 2022 | The p.R279H variant (also known as c.836G>A), located in coding exon 7 of the NEXN gene, results from a G to A substitution at nucleotide position 836. The arginine at codon 279 is replaced by histidine, an amino acid with highly similar properties. This alteration has been reported in a sudden unexplained death cohort (Lin Y et al. Circ Cardiovasc Genet, 2017 Dec;10:). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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