rs397517851
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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):c.1756_1758del(p.Lys586del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,676 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000062 ( 0 hom. )
Consequence
NEXN
NM_144573.4 inframe_deletion
NM_144573.4 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.47
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 9 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEXN | NM_144573.4 | c.1756_1758del | p.Lys586del | inframe_deletion | 13/13 | ENST00000334785.12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEXN | ENST00000334785.12 | c.1756_1758del | p.Lys586del | inframe_deletion | 13/13 | 1 | NM_144573.4 | P3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
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GnomAD3 exomes AF: 0.00000803 AC: 2AN: 249020Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135102
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GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461676Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727132
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GnomAD4 genome ? Cov.: 32
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
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 | May 31, 2012 | The Lys586del variant in NEXN has not been reported in the literature nor previo usly identified by our laboratory. This in-frame deletion removes the lysine (Ly s) residue at position 586. The NEXN gene has not been widely sequenced and the refore the types of variants leading to disease are not yet well characterized. Of note, our laboratory has identified single amino acid deletions in 3 individu als with DCM. In summary, additional information is needed to fully assess the c linical significance of the Lys586del variant. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Oct 16, 2019 | Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In-frame deletion of 1 amino acid in a non-repeat region; In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Identified in an individual with dilated cardiomyopathy, however, detailed clinical and segregation information was not provided, and it is unclear if this individual may have had variants identified in other genes (Walsh et al., 2017); This variant is associated with the following publications: (PMID: 27532257) - |
Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jul 21, 2018 | Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. This variant has been observed in an individual affected with dilated cardiomyopathy (PMID: 27532257). ClinVar contains an entry for this variant (Variation ID: 47896). This variant is present in population databases (rs771017447, ExAC 0.003%). This variant, c.1756_1758delAAG, results in the deletion of 1 amino acid of the NEXN protein (p.Lys586del), but otherwise preserves the integrity of the reading frame. 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