rs397517853
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Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PM4_SupportingBS1_SupportingBS2
The NM_144573.4(NEXN):c.1949_1951delGAG(p.Gly650del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000104 in 1,613,646 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. G650G) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )
Consequence
NEXN
NM_144573.4 disruptive_inframe_deletion
NM_144573.4 disruptive_inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.61
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 -2 ACMG points.
PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_144573.4
PM4
Nonframeshift variant in NON repetitive region in NM_144573.4. Strenght limited to Supporting due to length of the change: 1aa.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000855 (13/152132) while in subpopulation NFE AF= 0.000177 (12/67986). AF 95% confidence interval is 0.000102. There are 0 homozygotes in gnomad4. There are 8 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
High AC in GnomAd4 at 13 AD gene.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.0000855 AC: 13AN: 152132Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000113 AC: 28AN: 248144Hom.: 0 AF XY: 0.000134 AC XY: 18AN XY: 134668
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GnomAD4 exome AF: 0.000106 AC: 155AN: 1461514Hom.: 0 AF XY: 0.000124 AC XY: 90AN XY: 727056
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GnomAD4 genome 0.0000855 AC: 13AN: 152132Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8AN XY: 74326
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ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:4
| Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The NEXN p.Gly650del variant was identified in 6 of 2000 proband chromosomes (frequency: 0.003) from individuals with dilated cardiomyopathy and was not identified in 2502 control chromosomes from healthy individuals (Hassel_2009_PMID:19881492). No variants were identified in 9 other dilated cardiomyopathy genes in the 6 individuals carrying the p.G650del mutation. The variant was also identified in the mildly affected brother of one of the probands, as well as her 33-year-old unaffected daughter. In two other unrelated probands, both mothers had died of DCM and therefore DNA was unavailable, however both fathers were not carriers, suggesting that the affected mothers are obligate carriers of the p.G650del variant (Hassel_2009_PMID:19881492). The variant was identified in dbSNP (ID: rs1488731300) and ClinVar (classified as uncertain significance by Invitae, GeneDx, Laboratory for Molecular Medicine and CHEO Genetics Diagnostic Laboratory, and as likely pathogenic by Ambry Genetics). The variant was identified in control databases in 29 of 279530 chromosomes at a frequency of 0.0001037 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 27 of 127614 chromosomes (freq: 0.000212), Ashkenazi Jewish in 1 of 10306 chromosomes (freq: 0.000097) and Latino in 1 of 35332 chromosomes (freq: 0.000028), but was not observed in the African, East Asian, European (Finnish), Other or South Asian populations. This variant is an in-frame deletion resulting in the removal of a glycine (gly) residue at codon 650. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. Zebrafish with the p.G650del demonstrated a dilated cardiomyopathy phenotype (Hassel_2009_PMID:19881492). In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | May 01, 2023 | NEXN: PS4:Moderate, PM2:Supporting, PM4:Supporting, PS3:Supporting - |
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 01, 2021 | Reported in several individuals with dilated cardiomyopathy and one individual with unspecified arrhythmogenic disorder (Hassel et al., 2009; Marschall et al., 2019); Reported in ClinVar as a variant of uncertain significance by four other clinical laboratories, and reported as a likely benign variant by one laboratory (ClinVar Variant ID# 47899; Landrum et al., 2016); In-frame deletion of a glycine residue at codon 650, denoted p.G650del; in silico analysis supports a deleterious effect on protein structure/function; In vivo functional studies demonstrated that c.1949_1951delGAG resulted in cardiomyopathy and altered cell dynamics (Hassel et al., 2009; Liu et al., 2020); however, it is unclear whether these findings are of clinical relevance; This variant is associated with the following publications: (PMID: 20970104, 19881492, 32814711, 31737537) - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | Feb 06, 2024 | - - |
Dilated cardiomyopathy 1CC Pathogenic:1Uncertain:2
| Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2009 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Mendelics | Apr 11, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Victorian Clinical Genetics Services, Murdoch Childrens Research Institute | May 06, 2021 | Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as VUS-3B. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v2) <0.001 for a dominant condition (29 heterozygotes, 0 homozygotes). (SP) 0600 - Variant is located in the annotated IGcam domain (PMID: 19881492). (I) 0705 - No comparable inframe deletion variants have previous evidence for pathogenicity. (I) 0808 - Previous evidence of pathogenicity for this variant is conflicting. This variant has been reported multiple times as a VUS and once as likely benign, and has been observed in multiple unrelated individuals with dilated cardiomyopathy (DCM) (ClinVar, PMID: 19881492). (I) 0905 - No published segregation evidence has been identified for this variant. (I) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Animal models expressing this variant display the DCM phenotype, and analysis of affected tissue suggests that this variant results in reduced protein stability however, this is conflicting between publications (PMID: 19881492, PMID: 32814711). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign - |
not specified Uncertain:2
| Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 10, 2019 | The p.Gly650del variant in NEXN has been reported in the literature in 6 individuals with DCM. Currently there is insufficient evidence to conclude whether this variant segregates with disease in these families (Hassel 2009). This variant has also been identified by other clinical laboratories in 2 individuals with DCM (including an infant whose unaffected mother also harbored this variant), 1 individual with HCM, and 1 individual with an unspecified cardiomyopathy and segregated with DCM in one affected relative from one family (Ambry pers. comm, Invitae pers. comm., LMM data, ClinVar Variation ID # 47899). However, it has been identified in 0.02% (27/127614) European chromosomes by gnomAD (http://gnomad.broadinstitute.org/), which is a frequency defined by the ClinGen Inherited Cardiomyopathy Expert Panel Functional as being greater than expected for the disorder. Studies have shown that human hearts with this variant had disrupted sarcomeres and abnormal z-discs and this was also observed in zebrafish embryos injected with this variant that went on to develop severe cardiac dilation (Hassel 2009). This variant is a deletion of 1 amino acid at position 650 and is not predicted to alter the protein reading-frame. It is unclear if this deletion will impact the protein. In summary due to conflicting evidence, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS3_Moderate, PM4_Supporting, BS1_Supporting. - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Nov 07, 2023 | Variant summary: NEXN c.1949_1951delGAG (p.Gly650del) results in an in-frame deletion that is predicted to remove one amino acid from the immunoglobulin subtype domain (IPR003599) of the encoded protein. The variant allele was found at a frequency of 0.00011 in 248144 control chromosomes (gnomAD). The observed variant frequency is approximately 7-fold of the estimated maximal expected allele frequency for a pathogenic variant in NEXN causing Dilated Cardiomyopathy phenotype (1.6e-05), suggesting that the variant may be benign. c.1949_1951delGAG has been reported in the literature in multiple individuals affected with Dilated Cardiomyopathy, including those with a positive family history, but without sufficient genetic testing to establish whether the variant segregated in affected relatives, and several individuals reported with the variant had a mild phenotype and/or were asymptomatic (e.g. Hassel_2009, Marschall_2019, Bruyndonckx_2021). Experimental evidence evaluating an impact on protein function has been reported in a zebrafish and mouse model (e.g. Hassel_2009, Liu_2020). The variant resulted in a DCM phenotype in zebrafish and homozygous mice; however mice that were heterozygous for the variant did not develop signs of cardiac disease versus wild type controls, and the effect of the variant on nexin expression and stability was conflicting between these two studies. The clinical relevance of these findings is unclear and therefore does not allow convincing conclusions about the variant effect. The following publications have been ascertained in the context of this evaluation (PMID: 33949776, 19881492, 32814711, 31737537, 36129056). Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Cardiomyopathy Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Oct 11, 2022 | - - |
NEXN-related disorder Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 01, 2024 | The NEXN c.1949_1951delGAG variant is predicted to result in an in-frame deletion (p.Gly650del). The NEXN gene variant c.1949_1951delGAG is predicted to result in the deletion of one amino acid p.Gly650del. This variant has been reported at a frequency of ~0.011% in individuals in a large population database and has been reported in ClinVar with conflicting interpretations of pathogenicity (https://www.ncbi.nlm.nih.gov/clinvar/variation/47899/). This variant has been reported in six individuals with dilated cardiomyopathy (Hassel et al. 2009. PubMed ID: 19881492). Zebrafish studies indicate this variant may result in a disruption of NEXN function; however, it is unclear if this would apply to humans (Hassel et al. 2009. PubMed ID: 19881492). Based on these observations, the c.1949_1951delGAG variant is classified as uncertain. - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 28, 2022 | The c.1949_1951delGAG variant (also known as p.G650del) is located in coding exon 12 of the NEXN gene. This variant results from an in-frame deletion of 3 nucleotides at positions 1949 to 1951. This results in the in-frame deletion of a glycine residue at codon 650. A previously reported study of 1000 unrelated individuals with dilated cardiomyopathy (DCM) found 6 individuals that were heterozygous for p.G650del. Functional studies performed in the same study indicated that p.G650del overexpression in zebrafish disrupted sarcomeric units and destabilized Z-disks, but the clinical relevance of the overexpression study is unclear (Hassel D et al. Nat Med. 2009;15(11):1281-8). This variant has also been detected in a pediatric case with transient DCM as well as in a DCM cohort (Marschall C et al. Cardiovasc Diagn Ther. 2019 Oct;9(Suppl 2):S292-S298; Bruyndonckx L. Am J Med Genet A. 2021 Aug;185(8):2464-2470). A knock-in mouse model homozygous for the equivalent of this variant recapitulated DCM phenotype; however, heterozygous mice reportedly did not demonstrate phenotype (Liu C et al. JCI Insight. 2020 08;5(16)). This amino acid position is highly conserved in available vertebrate species; however, the neighboring glycine (p.G649) is poorly conserved. 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 | Labcorp Genetics (formerly Invitae), Labcorp | Sep 21, 2022 | This variant, c.1949_1951del, results in the deletion of 1 amino acid(s) of the NEXN protein (p.Gly650del), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs760927219, gnomAD 0.02%). This variant has been observed in individual(s) with clinical features of dilated cardiomyopathy (PMID: 19881492, 31737537, 33949776). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this variant affects NEXN function (PMID: 19881492, 32814711). 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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Find out detailed SpliceAI scores and Pangolin per-transcript scores at