rs876657928
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_SupportingBS2
The NM_144573.4(NEXN):βc.1820_1822delβ(p.Gly607del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000308 in 1,461,652 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: not found (cov: 32)
Exomes π: 0.000031 ( 0 hom. )
Consequence
NEXN
NM_144573.4 inframe_deletion
NM_144573.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 10.0
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 Likely_benign. Variant got -3 ACMG points.
PM4
?
Nonframeshift variant in NON repetitive region in NM_144573.4. Strenght limited to Supporting due to length of the change: 1aa.
BS2
?
High AC in GnomAdExome4 at 45 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEXN | NM_144573.4 | c.1820_1822del | p.Gly607del | inframe_deletion | 13/13 | ENST00000334785.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEXN | ENST00000334785.12 | c.1820_1822del | p.Gly607del | inframe_deletion | 13/13 | 1 | NM_144573.4 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
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GnomAD3 exomes AF: 0.0000321 AC: 8AN: 248994Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135096
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GnomAD4 exome AF: 0.0000308 AC: 45AN: 1461652Hom.: 0 AF XY: 0.0000344 AC XY: 25AN XY: 727136
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, multiple submitters, no conflicts
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 | Oct 01, 2015 | The p.Gly607del variant in NEXN has not been previously reported in individuals with cardiomyopathy but has been identified in 3/66474 European chromosomes by t he Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org). This var iant is a deletion of 1 amino acid at position 607. It is unclear if this deleti on will impact the protein. In summary, the clinical significance of the p.Gly60 7del variant is uncertain. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 12, 2017 | A variant of uncertain significance has been identified in the NEXN gene. The c.1820_1822delGAG variant has not been published as pathogenic or been reported as benign to our knowledge. The c.1820_1822delGAG variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.1820_1822delGAG variant results in an in-frame deletion of a Glycine residue at codon 607, denoted p.Gly607del, and does not result in a shift in the reading frame or a premature stop codon. No nearby in-frame deletions in the NEXN gene have been reported in the Human Gene Mutation Database (HGMD) in association with cardiomyopathy, and the majority of variants in the NEXN gene reported in HGMD are missense variants (Stenson et al., 2014). However, in silico analysis predicts this variant is probably damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is pathogenic or rare benign. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 14, 2022 | The c.1820_1822delGAG variant (also known as p.G607del) is located in coding exon 12 of the NEXN gene. This variant results from an in-frame GAG deletion at nucleotide positions 1820 to 1822. This results in the in-frame deletion of a glycine residue at codon 607. This variant has been reported in dilated cardiomyopathy (DCM) and left ventricular non-compaction (LVNC) cohorts (Mazzarotto F et al. Circulation, 2020 02;141:387-398; Mazzarotto F et al. Genet Med, 2021 05;23:856-864).This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis (Choi Y et al., PLoS ONE 2012; 7(10):e46688). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jun 13, 2022 | This variant, c.1820_1822del, results in the deletion of 1 amino acid(s) of the NEXN protein (p.Gly607del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs774370743, gnomAD 0.006%). This variant has been observed in individual(s) with dilated cardiomyopathy and/or left ventricular noncompaction (PMID: 31983221, 33500567). ClinVar contains an entry for this variant (Variation ID: 229055). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at