rs368268112
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_006393.3(NEBL):c.82-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000477 in 1,613,102 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00021 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00051 ( 0 hom. )
Consequence
NEBL
NM_006393.3 splice_region, intron
NM_006393.3 splice_region, intron
Scores
2
Splicing: ADA: 0.8653
2
Clinical Significance
Conservation
PhyloP100: -0.149
Genes affected
NEBL (HGNC:16932): (nebulette) This gene encodes a nebulin like protein that is abundantly expressed in cardiac muscle. The encoded protein binds actin and interacts with thin filaments and Z-line associated proteins in striated muscle. This protein may be involved in cardiac myofibril assembly. A shorter isoform of this protein termed LIM nebulette is expressed in non-muscle cells and may function as a component of focal adhesion complexes. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.81).
BP6
Variant 10-20897033-T-C is Benign according to our data. Variant chr10-20897033-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 164771.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}. Variant chr10-20897033-T-C is described in Lovd as [Likely_benign].
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NEBL | NM_006393.3 | c.82-4A>G | splice_region_variant, intron_variant | ENST00000377122.9 | NP_006384.1 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NEBL | ENST00000377122.9 | c.82-4A>G | splice_region_variant, intron_variant | 1 | NM_006393.3 | ENSP00000366326.4 |
Frequencies
GnomAD3 genomes 0.000210 AC: 32AN: 152112Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000255 AC: 64AN: 251270Hom.: 0 AF XY: 0.000250 AC XY: 34AN XY: 135808
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GnomAD4 exome AF: 0.000505 AC: 738AN: 1460990Hom.: 0 Cov.: 31 AF XY: 0.000508 AC XY: 369AN XY: 726876
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GnomAD4 genome 0.000210 AC: 32AN: 152112Hom.: 0 Cov.: 32 AF XY: 0.000135 AC XY: 10AN XY: 74308
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 30, 2015 | c.82-4A>G in intron 1 of NEBL: This variant is not expected to have clinical sig nificance because it is not located within the splice consensus sequence. It ha s been identified in 25/66724 European chromosomes by the Exome Aggregation Con sortium (ExAC, http://exac.broadinstitute.org; dbSNP rs368268112). - |
| Uncertain significance, no assertion criteria provided | clinical testing | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Jul 09, 2014 | 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. IVS1-4 A>G (c.82-4 A>G) in NEBL (NM_006393.2) Given weak gene-disease association and the lack of available data on the specific variant we consider this variant a variant of uncertain significance. NEBL encodes nebulette, which aligns thin filaments and connects them with the myocardial Z-disk. It is a cardiac-specific member of the nebulin protein family, which all have "nebulin-repeats" that bind a single actin subunit and are involved in tropomyosin-troponin assembly. Arimura et al 200 sequenced NEBL in patients with DCM using a candidate gene approach and noted that one common variant, p.Asn654Lys, was more frequently seen in the homozygote state in patients with sporadic (but not familial) DCM than in controls. NEBL was one of 20 candidate genes analyzed in 260 DCM patients from the pediatric cardiomyopathy registry (Purevjav et al 2010). They found four missense variants in their patients which were absent in 300 controls, however three of these are in the ESP dataset and for the fourth there is another variant at the same codon present in ESP. Segregation data was not provided. They did construct transgenic mouse models that did show a cardiomyopathy phenotype. At least one of the patients also had endocardial fibroelastosis. I could find no studies reporting on linkage, segregation, or increased burden of rare NEBL variants in cardiomyopathy patients as compared to controls. I could find no reports of this specific variant in association with disease. The variant is not listed in ClinVar (as of July 9th, 2014). The variant was reported online in 6 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of July 9th, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). The variant is in dbSNP (rs368268112), pointing to the ESP data. - |
not provided Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 21, 2024 | In silico analysis supports a deleterious effect on splicing; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (PMID: 25741868) - |
Cardiovascular phenotype Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 14, 2013 | The c.82-4A>G variant is located in the NEBL gene. This alteration results from an A to G substitution 4 nucleotides before coding exon 2. ​Based on data from the NHLBI Exome Sequencing Project (ESP), the G-allele has an overall frequency of approximately 0.05% (6/13006),havingnot been observed in 4406 of African American alleles, but observed in 0.07% (6/8600) of European American alleles. This variant was not found in the following population databases: dbSNP database or the 1000 Genomes Project.This nucleotide position is poorly conserved in available vertebrate species.Using the BDGP and ESEfinder splice site prediction tools, this alteration does not have any significant effect on the native acceptor splice site; however, direct evidence is unavailable.Since supporting evidence is limited at this time, the clinical significance ofc.82-4A>Gremains unclear. - |
Primary dilated cardiomyopathy Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 08, 2024 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at