1-77935986-CAAG-C
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM4_SupportingBS1_SupportingBS2
The NM_144573.4(NEXN):c.1419_1421delAAG(p.Arg474del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000121 in 1,613,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R473R) has been classified as Likely benign.
Frequency
Consequence
NM_144573.4 disruptive_inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.000132 AC: 20AN: 151988Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000173 AC: 43AN: 249020Hom.: 0 AF XY: 0.000207 AC XY: 28AN XY: 135224
GnomAD4 exome AF: 0.000120 AC: 176AN: 1461684Hom.: 0 AF XY: 0.000138 AC XY: 100AN XY: 727132
GnomAD4 genome AF: 0.000132 AC: 20AN: 151988Hom.: 0 Cov.: 33 AF XY: 0.0000943 AC XY: 7AN XY: 74236
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Jan 23, 2023 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 03, 2023 | Reported in an individual with DCM (Gigli et al., 2019); described as c.1416_1418delAAG (p.Arg475del); In-frame deletion of one amino acid in a non-repeat region; In silico analysis supports a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 31514951) - |
not specified Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | May 22, 2013 | Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. p. Arg474del (c.1419_1421delAAG) This variant is novel. This variant is located in exon 11 (coding exon 10) of the NEXN gene. The variant results from an in-frame AAG deletion between nucleotide position 1419 and 1421. This results in the deletion of an arginine residue at codon 474. The arginine at codon 474 is conserved across species, as are neighboring amino acids. In total the variant has not been seen in ~6,500 published controls and individuals from publicly available population datasets. There is no variation at codon 474 listed in the NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 8/1/13). There is also no variation at this codon listed in dbSNP or 1000 genomes (as of 8/1/13). Ambry genetics did not include internal control data. - |
Cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Mar 01, 2019 | - - |
Primary familial dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | - | - - |
NEXN-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 15, 2024 | The NEXN c.1419_1421delAAG variant is predicted to result in an in-frame deletion (p.Arg475del). This variant was reported in individuals with dilated cardiomyopathy or sudden death; however, no additional studies were performed to help assess the pathogenicity of this variant (Scheiper et al. 2018. PubMed ID: 30415094; Online supplementary file 2, van Lint et al. 2019. PubMed ID: 30847666; described as c.1416_1418delAAG in Online Table 1, Gigli et al. 2019. PubMed ID: 31514951). This variant is reported in 0.020% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations of pathogenicity in ClinVar ranging from likely benign to uncertain (http://www.ncbi.nlm.nih.gov/clinvar/variation/201940). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Dilated cardiomyopathy 1CC;C3151267:Hypertrophic cardiomyopathy 20 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 11, 2023 | This variant, c.1419_1421del, results in the deletion of 1 amino acid(s) of the NEXN protein (p.Arg475del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs766608869, gnomAD 0.02%). This variant has been observed in individual(s) with dilated cardiomyopathy (PMID: 31514951). ClinVar contains an entry for this variant (Variation ID: 201940). 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. - |
Cardiovascular phenotype Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 23, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at