chr1-77917989-G-C
Variant summary
Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_144573.4(NEXN):c.249G>C(p.Glu83Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. E83K) has been classified as Uncertain significance.
Frequency
Consequence
NM_144573.4 missense
Scores
Clinical Significance
Conservation
Publications
- dilated cardiomyopathyInheritance: AD Classification: MODERATE Submitted by: ClinGen
- familial isolated dilated cardiomyopathyInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- dilated cardiomyopathy 1CCInheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
- hypertrophic cardiomyopathyInheritance: AD Classification: LIMITED Submitted by: ClinGen
- hypertrophic cardiomyopathy 20Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
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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: 0.00000401 AC: 1AN: 249374 AF XY: 0.00000739 show subpopulations
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant classified as Uncertain Significance - Favor Benign. The Glu83Asp varian t in NEXN has not been reported in the literature nor previously identified by o ur laboratory. This variant has also not been identified in large and broad Euro pean American and African American populations by the NHLBI Exome Sequencing Pro ject (http://evs.gs.washington.edu/EVS). Glutamic acid (Glu) is not highly conse rved across evolutionarily distant species, and the change to Aspartic Acid (Asp ) is present in several species, increasing the likelihood that this change woul d be tolerated. Computational analyses (biochemical amino acid properties, Align GVGD, PolyPhen2, and SIFT) suggest that the Glu83Asp variant may not impact the protein, though this information is not predictive enough to rule out pathogenic ity. Although this data supports that the Glu83Asp variant may be benign, additi onal studies are needed to fully assess its clinical significance. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at