chr2-151602679-C-T
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_ModerateBP6
The NM_001164507.2(NEB):c.13276G>A(p.Asp4426Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00039 ( 0 hom., cov: 0)
Exomes 𝑓: 0.000089 ( 1 hom. )
Failed GnomAD Quality Control
Consequence
NEB
NM_001164507.2 missense
NM_001164507.2 missense
Scores
2
13
Clinical Significance
Conservation
PhyloP100: 1.70
Genes affected
NEB (HGNC:7720): (nebulin) This gene encodes nebulin, a giant protein component of the cytoskeletal matrix that coexists with the thick and thin filaments within the sarcomeres of skeletal muscle. In most vertebrates, nebulin accounts for 3 to 4% of the total myofibrillar protein. The encoded protein contains approximately 30-amino acid long modules that can be classified into 7 types and other repeated modules. Protein isoform sizes vary from 600 to 800 kD due to alternative splicing that is tissue-, species-,and developmental stage-specific. Of the 183 exons in the nebulin gene, at least 43 are alternatively spliced, although exons 143 and 144 are not found in the same transcript. Of the several thousand transcript variants predicted for nebulin, the RefSeq Project has decided to create three representative RefSeq records. Mutations in this gene are associated with recessive nemaline myopathy. [provided by RefSeq, Sep 2009]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.21040237).
BP6
Variant 2-151602679-C-T is Benign according to our data. Variant chr2-151602679-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 227726.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Benign=1, Uncertain_significance=1}. Variant chr2-151602679-C-T is described in Lovd as [Benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.13276G>A | p.Asp4426Asn | missense_variant | 87/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.13276G>A | p.Asp4426Asn | missense_variant | 87/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.13276G>A | p.Asp4426Asn | missense_variant | 87/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.13276G>A | p.Asp4426Asn | missense_variant | 87/182 | 5 | NM_001164507.2 | A2 | |
NEB | ENST00000409198.5 | c.11601+7130G>A | intron_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 2AN: 5074Hom.: 0 Cov.: 0 FAILED QC
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GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000889 AC: 6AN: 67488Hom.: 1 Cov.: 0 AF XY: 0.0000840 AC XY: 3AN XY: 35698
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GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000394 AC: 2AN: 5076Hom.: 0 Cov.: 0 AF XY: 0.000432 AC XY: 1AN XY: 2314
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Sep 17, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 15, 2023 | - - |
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Dec 19, 2014 | NEB exons 82-105 are organized in three repetitive blocks of 8 exons each and be cause these blocks are nearly identical in sequence, homologous exons (e.g., exo ns 82, 90, and 98) are co-amplified and sequenced (each amplicon consists of 6 a lleles). This variant represents a nonhomologous position within the three repet itive blocks (c.13276G, c.14734A, and c.16192G). The variable alleles at this po sition are not expected to have clinical significance due to a lack of conservat ion at this position across species, including mammals. A change at this positio n has also been identified in 0.4% (41/10774) to 15% (3900/21678) of chromosomes across several diverse populations by the Exome Aggregate Consortium (http://ex ac.broadinstitute.org/). - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Nemaline myopathy 2 Benign:1
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;T;T;.;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;N;N
PROVEAN
Benign
N;.;N;.;.
REVEL
Benign
Sift
Uncertain
D;.;D;.;.
Sift4G
Uncertain
D;D;D;D;D
Vest4
MutPred
Loss of phosphorylation at Y4424 (P = 0.1443);Loss of phosphorylation at Y4424 (P = 0.1443);Loss of phosphorylation at Y4424 (P = 0.1443);Loss of phosphorylation at Y4424 (P = 0.1443);Loss of phosphorylation at Y4424 (P = 0.1443);
MVP
MPC
0.31
ClinPred
T
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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