rs748561855
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001164507.2(NEB):c.24742C>T(p.Arg8248Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000869 in 1,611,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R8248H) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000075 ( 0 hom. )
Consequence
NEB
NM_001164507.2 missense
NM_001164507.2 missense
Scores
7
8
4
Clinical Significance
Conservation
PhyloP100: 4.22
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]
RIF1 (HGNC:23207): (replication timing regulatory factor 1) This gene encodes a protein that shares homology with the yeast teleomere binding protein, Rap1 interacting factor 1. This protein localizes to aberrant telomeres may be involved in DNA repair. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.24742C>T | p.Arg8248Cys | missense_variant | 176/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.24742C>T | p.Arg8248Cys | missense_variant | 176/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.24742C>T | p.Arg8248Cys | missense_variant | 176/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.24742C>T | p.Arg8248Cys | missense_variant | 176/182 | 5 | NM_001164507.2 | A2 |
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152044Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000403 AC: 1AN: 248186Hom.: 0 AF XY: 0.00000743 AC XY: 1AN XY: 134634
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GnomAD4 exome AF: 0.00000754 AC: 11AN: 1459818Hom.: 0 Cov.: 30 AF XY: 0.00000689 AC XY: 5AN XY: 726184
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GnomAD4 genome AF: 0.0000197 AC: 3AN: 152044Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74246
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Nemaline myopathy 2 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 01, 2021 | This sequence change replaces arginine with cysteine at codon 8283 of the NEB protein (p.Arg8283Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs748561855, ExAC 0.002%). 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. | Sep 16, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Dec 13, 2022 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
.;.;T;.;T;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D;.;.
M_CAP
Benign
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Uncertain
T
MutationAssessor
Pathogenic
M;.;.;.;M;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;.;D;D;.;.
REVEL
Uncertain
Sift
Uncertain
D;D;.;D;D;.;.
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
1.0
.;.;.;.;D;.;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0102);.;.;.;Loss of MoRF binding (P = 0.0102);.;.;
MVP
MPC
0.39
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -23
Find out detailed SpliceAI scores and Pangolin per-transcript scores at