rs201111610
Positions:
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_001164508.2(NEB):c.16637G>A(p.Arg5546His) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 12/17 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 0.012 ( 12 hom., cov: 19)
Exomes 𝑓: 0.0020 ( 589 hom. )
Failed GnomAD Quality Control
Consequence
NEB
NM_001164508.2 missense
NM_001164508.2 missense
Scores
16
Clinical Significance
Conservation
PhyloP100: 2.79
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -5 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.03037572).
BP6
Variant 2-151579405-C-T is Benign according to our data. Variant chr2-151579405-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 257765.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1, Likely_benign=1}. Variant chr2-151579405-C-T is described in Lovd as [Likely_benign].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.16637G>A | p.Arg5546His | missense_variant | 105/182 | ENST00000427231.7 | NP_001157979.2 | |
NEB | NM_001164508.2 | c.16637G>A | p.Arg5546His | missense_variant | 105/182 | ENST00000397345.8 | NP_001157980.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.16637G>A | p.Arg5546His | missense_variant | 105/182 | 5 | NM_001164508.2 | ENSP00000380505 | P5 | |
NEB | ENST00000427231.7 | c.16637G>A | p.Arg5546His | missense_variant | 105/182 | 5 | NM_001164507.2 | ENSP00000416578 | A2 | |
NEB | ENST00000413693.5 | c.827G>A | p.Arg276His | missense_variant | 5/74 | 5 | ENSP00000410961 | |||
NEB | ENST00000409198.5 | c.11602-3051G>A | intron_variant | 5 | ENSP00000386259 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 1669AN: 136432Hom.: 12 Cov.: 19 FAILED QC
GnomAD3 genomes
AF:
AC:
1669
AN:
136432
Hom.:
Cov.:
19
FAILED QC
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.000925 AC: 143AN: 154636Hom.: 47 AF XY: 0.000770 AC XY: 63AN XY: 81786
GnomAD3 exomes
AF:
AC:
143
AN:
154636
Hom.:
AF XY:
AC XY:
63
AN XY:
81786
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00199 AC: 2701AN: 1356718Hom.: 589 Cov.: 32 AF XY: 0.00200 AC XY: 1336AN XY: 669282
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
2701
AN:
1356718
Hom.:
Cov.:
32
AF XY:
AC XY:
1336
AN XY:
669282
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0122 AC: 1669AN: 136554Hom.: 12 Cov.: 19 AF XY: 0.0111 AC XY: 734AN XY: 66370
GnomAD4 genome
Data not reliable, filtered out with message: AS_VQSR
AF:
AC:
1669
AN:
136554
Hom.:
Cov.:
19
AF XY:
AC XY:
734
AN XY:
66370
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:3
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 29, 2021 | This variant is associated with the following publications: (PMID: 25203624) - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Peripheral neuropathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Claritas Genomics | Aug 22, 2016 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jan 22, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Benign
.;T;.;T;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T;T;.;.
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T
MetaSVM
Benign
T
MutationTaster
Benign
D;D;N;N
PROVEAN
Benign
N;.;N;N;.;.
REVEL
Benign
Sift
Benign
T;.;T;T;.;.
Sift4G
Benign
T;T;T;T;T;T
Vest4
MVP
MPC
0.061
ClinPred
T
GERP RS
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