rs727504874
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The ENST00000334785.12(NEXN):c.1181_1182del(p.Glu394GlyfsTer6) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. T393T) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Consequence
NEXN
ENST00000334785.12 frameshift
ENST00000334785.12 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.00
Genes affected
NEXN (HGNC:29557): (nexilin F-actin binding protein) This gene encodes a filamentous actin-binding protein that may function in cell adhesion and migration. Mutations in this gene have been associated with dilated cardiomyopathy, also known as CMD1CC. Alternatively spliced transcript variants have been described.[provided by RefSeq, Feb 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 10 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEXN | NM_144573.4 | c.1181_1182del | p.Glu394GlyfsTer6 | frameshift_variant | 10/13 | ENST00000334785.12 | NP_653174.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEXN | ENST00000334785.12 | c.1181_1182del | p.Glu394GlyfsTer6 | frameshift_variant | 10/13 | 1 | NM_144573.4 | ENSP00000333938 | P3 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jan 22, 2014 | Variant classified as Uncertain Significance - Favor Pathogenic. The Glu394fs va riant in NEXN has not been previously reported in individuals with cardiomyopath y and data from large population studies is insufficient to assess its frequency . This frameshift variant is predicted to alter the protein?s amino acid sequenc e beginning at position 394 and lead to a premature termination codon 6 amino ac ids downstream. This alteration is then predicted to lead to a truncated or abse nt protein. Although the severe nature of the change increases the likelihood th at the variant is pathogenic, the NEXN gene has not been widely studied and the spectrum of variants leading to disease is not well-defined. Loss-of-function o f NEXN has been shown to cause DCM in animal models, however, it remains unclear if one or both copies of the gene need to be affected to cause disease. In summ ary, additional information is needed to fully assess the clinical significance of this variant. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at