1-77942120-GAGAAGA-GAGA
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP3BS2
The ENST00000334785.12(NEXN):c.1582_1584del(p.Glu528del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00013 in 1,613,586 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
NEXN
ENST00000334785.12 inframe_deletion
ENST00000334785.12 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.11
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 -5 ACMG points.
BP3
Nonframeshift variant in repetitive region in ENST00000334785.12
BS2
High AC in GnomAd4 at 24 AD gene.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NEXN | NM_144573.4 | c.1582_1584del | p.Glu528del | inframe_deletion | 12/13 | ENST00000334785.12 | NP_653174.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NEXN | ENST00000334785.12 | c.1582_1584del | p.Glu528del | inframe_deletion | 12/13 | 1 | NM_144573.4 | ENSP00000333938 | P3 |
Frequencies
GnomAD3 genomes 0.000158 AC: 24AN: 152080Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000153 AC: 38AN: 248710Hom.: 0 AF XY: 0.000133 AC XY: 18AN XY: 134980
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GnomAD4 exome AF: 0.000127 AC: 186AN: 1461506Hom.: 0 AF XY: 0.000117 AC XY: 85AN XY: 727054
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GnomAD4 genome 0.000158 AC: 24AN: 152080Hom.: 0 Cov.: 32 AF XY: 0.000148 AC XY: 11AN XY: 74292
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:13Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4Benign:3
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 04, 2024 | In silico analysis supports a deleterious effect on protein structure/function; In-frame deletion of 1 amino acid in a repetitive region with no known function; This variant is associated with the following publications: (PMID: 26582918, 37298070) - |
| Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
| Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
| Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jul 07, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 22, 2014 | - - |
Dilated cardiomyopathy 1CC Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 26, 2024 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The inframe deletion c.1582_1584del (p.Glu528del) has been observed in individual(s) with dilated cardiomyopathy (Kuhnisch J, et.al.,2019).This variant has been reported to the ClinVar database as Uncertain Significance. The p.Glu528del variant is novel (not in any individuals) in 1000 Genomes and allele frequency of 0.01535% is reported in gnomAD. This p.Glu528del causes deletion of amino acid Glutamic Acid at position 528. For these reasons, this variant has been classified as Uncertain Significance . - |
Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Sep 08, 2021 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | This variant, c.1582_1584del, results in the deletion of 1 amino acid(s) of the NEXN protein (p.Glu528del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs770868024, gnomAD 0.03%). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 31568572; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.1572_1574delAGA (p.E525del). ClinVar contains an entry for this variant (Variation ID: 194130). 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. - |
not specified Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 12, 2015 | Variant classified as Uncertain Significance - Favor Pathogenic. The p.Glu528del variant has been identified in 2 consanguineous families of Middle Eastern anc estry as homozygous in 5 affected siblings (Conference abstract by Al-Hassnan 20 13, LMM unpublished data). This variant has also been identified as heterozygous in 14/65856 European chromosomes by the Exome Aggregation Consortium (ExAC, htt p://exac.broadinstitute.org). This variant is a deletion of 1 amino acid at posi tion 528 from a string of 4 glutamic acids. It is unclear if this deletion will impact the protein. In summary, while there is some suspicion for a pathogenic r ole, the clinical significance of the p.Glu528del variant is uncertain. - |
| Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | May 13, 2020 | - - |
Primary dilated cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | research | Klaassen Lab, Charite University Medicine Berlin | Jul 03, 2019 | - - |
NEXN-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 04, 2024 | The NEXN c.1582_1584delGAA variant is predicted to result in an in-frame deletion (p.Glu528del). This variant, also described as c.1572_1574delAGA, has been reported in the homozygous state in at least five individuals with dilated cardiomyopathy (DCM) including two sibling pairs (Al-Hassnan et al. 2013. DOI: 10.1016/j.jsha.2013.03.180; Tables S4 & S5, Kühnisch et al. 2019. PubMed ID: 31568572; Al Mansoori et al. 2023. PubMed ID: 37298070). It has also been reported in the heterozygous state in an individual with DCM and left ventricular non-compaction (LVNC) who was homozygous for a splice-altering, loss-of-function variant in the TNNI3 gene (Tables S4 & S5, Kühnisch et al. 2019. PubMed ID: 31568572). This variant is reported in 0.036% of alleles in individuals of East Asian descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 22, 2022 | The c.1582_1584delGAA variant (also known as p.E528del) is located in coding exon 11 of the NEXN gene. This variant results from an in-frame GAA deletion at nucleotide positions 1582 to 1584. This results in the in-frame deletion of a glutamic acid at codon 528. This variant was reportedly detected in the homozygous state in two siblings with severe, pediatric onset dilated cardiomyopathy (Bruyndonckx L et al. Am J Med Genet A. 2021 08;185(8):2464-2470). This variant, also referred to as p.E525del, was detected in a homozygous proband with DCM and in the heterozygous state in a proband with DCM and noncompaction cardiomyopathy who was also homozygous for a variant in the TNNI3 gene (Kühnisch J. Clin Genet. 2019 12;96(6):549-559). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be inconclusive 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. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at