rs200251444
Positions:
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBP6
The NM_001164507.2(NEB):c.6088C>T(p.Leu2030Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,596,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00054 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000065 ( 0 hom. )
Consequence
NEB
NM_001164507.2 missense
NM_001164507.2 missense
Scores
4
14
Clinical Significance
Conservation
PhyloP100: 1.46
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.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.01780811).
BP6
?
Variant 2-151658078-G-A is Benign according to our data. Variant chr2-151658078-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465622.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.6088C>T | p.Leu2030Phe | missense_variant | 48/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.6088C>T | p.Leu2030Phe | missense_variant | 48/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.6088C>T | p.Leu2030Phe | missense_variant | 48/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.6088C>T | p.Leu2030Phe | missense_variant | 48/182 | 5 | NM_001164507.2 | A2 | |
NEB | ENST00000409198.5 | c.6088C>T | p.Leu2030Phe | missense_variant | 48/150 | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.000545 AC: 83AN: 152164Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000128 AC: 30AN: 233848Hom.: 0 AF XY: 0.000103 AC XY: 13AN XY: 126380
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GnomAD4 exome AF: 0.0000651 AC: 94AN: 1443892Hom.: 0 Cov.: 29 AF XY: 0.0000599 AC XY: 43AN XY: 718062
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GnomAD4 genome ? AF: 0.000538 AC: 82AN: 152282Hom.: 0 Cov.: 32 AF XY: 0.000470 AC XY: 35AN XY: 74450
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:3Benign:1
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 21, 2016 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jun 28, 2024 | In silico analysis indicates that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The NEB p.Leu2030Phe variant was not identified in the literature nor was it identified in Cosmic, MutDB or LOVD 3.0. The variant was identified in dbSNP (ID: rs200251444) and in ClinVar with conflicting interpretations of pathogenicity (classified as likely benign by Invitae and uncertain significance by EGL Genetic diagnostics). The variant is associated with Nemaline myopathy 2. The variant was identified in control databases in 45 of 265236 chromosomes at a frequency of 0.00017 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 40 of 23168 chromosomes (freq: 0.001727), Latino in 5 of 33694 chromosomes (freq: 0.000148), while the variant was not observed in the Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Other, and South Asian populations. The p.Leu2030 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. 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. 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. - |
Likely benign, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 29, 2023 | - - |
NEB-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jul 30, 2023 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Nemaline myopathy 2 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 24, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;D;D;D;T;.;.
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;M;M;M;M
MutationTaster
Benign
N;N;N;N
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.;N;N;.;.
REVEL
Benign
Sift
Benign
T;T;.;T;T;.;.
Sift4G
Benign
T;T;T;T;T;T;T
Polyphen
0.87
.;.;.;.;P;.;.
Vest4
MVP
MPC
0.29
ClinPred
T
GERP RS
Varity_R
gMVP
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