rs1553966356
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6
The NM_001164508.2(NEB):āc.8598C>Gā(p.Asp2866Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,702 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 32)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
NEB
NM_001164508.2 missense
NM_001164508.2 missense
Scores
8
11
Clinical Significance
Conservation
PhyloP100: 0.843
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 Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP6
Variant 2-151640442-G-C is Benign according to our data. Variant chr2-151640442-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 514652.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.8598C>G | p.Asp2866Glu | missense_variant | 61/182 | ENST00000427231.7 | NP_001157979.2 | |
NEB | NM_001164508.2 | c.8598C>G | p.Asp2866Glu | missense_variant | 61/182 | ENST00000397345.8 | NP_001157980.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.8598C>G | p.Asp2866Glu | missense_variant | 61/182 | 5 | NM_001164508.2 | ENSP00000380505.3 | ||
NEB | ENST00000427231.7 | c.8598C>G | p.Asp2866Glu | missense_variant | 61/182 | 5 | NM_001164507.2 | ENSP00000416578.2 | ||
NEB | ENST00000409198.5 | c.8598C>G | p.Asp2866Glu | missense_variant | 61/150 | 5 | ENSP00000386259.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461702Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 727134
GnomAD4 exome
AF:
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1
AN:
1461702
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Cov.:
32
AF XY:
AC XY:
0
AN XY:
727134
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Nemaline myopathy 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 01, 2021 | This sequence change replaces aspartic acid with glutamic acid at codon 2866 of the NEB protein (p.Asp2866Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with NEB-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 28, 2020 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jan 15, 2018 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;.;T;.;T;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T;T;T;T;.;.
M_CAP
Benign
T
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.;M;M;M;M
PrimateAI
Benign
T
PROVEAN
Benign
N;N;.;N;N;.;.
REVEL
Benign
Sift
Benign
T;T;.;T;T;.;.
Sift4G
Uncertain
D;D;D;D;D;D;D
Polyphen
0.99
.;.;.;.;D;.;.
Vest4
MutPred
Gain of catalytic residue at D2866 (P = 0.0644);Gain of catalytic residue at D2866 (P = 0.0644);Gain of catalytic residue at D2866 (P = 0.0644);Gain of catalytic residue at D2866 (P = 0.0644);Gain of catalytic residue at D2866 (P = 0.0644);Gain of catalytic residue at D2866 (P = 0.0644);Gain of catalytic residue at D2866 (P = 0.0644);
MVP
MPC
0.21
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at