rs1394078245
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_001164507.2(NEB):c.17865T>G(p.His5955Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. H5955H) has been classified as Likely benign.
Frequency
Genomes: not found (cov: 32)
Consequence
NEB
NM_001164507.2 missense
NM_001164507.2 missense
Scores
7
11
Clinical Significance
Conservation
PhyloP100: -0.107
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;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.26604384).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.17865T>G | p.His5955Gln | missense_variant | 114/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.17865T>G | p.His5955Gln | missense_variant | 114/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.17865T>G | p.His5955Gln | missense_variant | 114/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.17865T>G | p.His5955Gln | missense_variant | 114/182 | 5 | NM_001164507.2 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 31
GnomAD4 exome
Cov.:
31
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Nemaline myopathy 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 19, 2018 | This sequence change replaces histidine with glutamine at codon 5955 of the NEB protein (p.His5955Gln). The histidine residue is moderately conserved and there is a small physicochemical difference between histidine and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NEB-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;D;D;D;T;D;.;.
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L;.;.;.;L;.;.;.
MutationTaster
Benign
N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;N;.;D;D;D;.;.
REVEL
Uncertain
Sift
Uncertain
D;D;.;D;D;D;.;.
Sift4G
Uncertain
D;D;D;D;D;D;D;D
Polyphen
0.46
.;.;.;.;P;.;.;.
Vest4
MutPred
Gain of methylation at K4251 (P = 0.0786);.;.;.;Gain of methylation at K4251 (P = 0.0786);.;.;.;
MVP
MPC
0.29
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