rs972622200
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1PM2
The NM_006393.3(NEBL):āc.2T>Cā(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.0000114 in 1,580,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.000012 ( 0 hom. )
Consequence
NEBL
NM_006393.3 start_lost
NM_006393.3 start_lost
Scores
2
8
6
Clinical Significance
Conservation
PhyloP100: 3.88
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 Pathogenic. Variant got 10 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEBL | NM_006393.3 | c.2T>C | p.Met1? | start_lost | 1/28 | ENST00000377122.9 | NP_006384.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEBL | ENST00000377122.9 | c.2T>C | p.Met1? | start_lost | 1/28 | 1 | NM_006393.3 | ENSP00000366326.4 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 151970Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000492 AC: 10AN: 203270Hom.: 0 AF XY: 0.0000366 AC XY: 4AN XY: 109348
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GnomAD4 exome AF: 0.0000119 AC: 17AN: 1428620Hom.: 0 Cov.: 31 AF XY: 0.0000113 AC XY: 8AN XY: 708778
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 151970Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74218
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 20, 2015 | A variant of uncertain significance has been identified in the NEBL gene. The c.2 T>C variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. This variant alters the initiator Methionine residue and the resultant protein would be described as p.Met1?" using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Met. The c.2 T>C variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. However, only four missense variants and no truncating variants in the NEBL gene have been reported in the Human Gene Mutation Database in association with disease (Stenson et al., 2014).Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant" - |
Primary dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 20, 2022 | This sequence change affects the initiator methionine of the NEBL mRNA. The next in-frame methionine is located at codon 39. This variant is present in population databases (no rsID available, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with NEBL-related conditions. ClinVar contains an entry for this variant (Variation ID: 488779). 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. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Pathogenic
D
Sift4G
Uncertain
D
Polyphen
P
Vest4
MutPred
Loss of stability (P = 0.0151);
MVP
ClinPred
D
GERP RS
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Splicing
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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