2-151493859-G-C
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001164507.2(NEB):āc.24588C>Gā(p.Tyr8196Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000899 in 1,557,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ā ). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: š 0.0000066 ( 0 hom., cov: 32)
Exomes š: 0.0000093 ( 0 hom. )
Consequence
NEB
NM_001164507.2 stop_gained
NM_001164507.2 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 6.26
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 Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 2-151493859-G-C is Pathogenic according to our data. Variant chr2-151493859-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 432817.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.24588C>G | p.Tyr8196Ter | stop_gained | 175/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.24588C>G | p.Tyr8196Ter | stop_gained | 175/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.24588C>G | p.Tyr8196Ter | stop_gained | 175/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.24588C>G | p.Tyr8196Ter | stop_gained | 175/182 | 5 | NM_001164507.2 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152058Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000221 AC: 4AN: 180836Hom.: 0 AF XY: 0.0000417 AC XY: 4AN XY: 96016
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GnomAD4 exome AF: 0.00000925 AC: 13AN: 1405200Hom.: 0 Cov.: 30 AF XY: 0.0000101 AC XY: 7AN XY: 694806
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GnomAD4 genome AF: 0.00000658 AC: 1AN: 152058Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74262
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Nemaline myopathy 2 Pathogenic:4
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Nov 09, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Genomics England Pilot Project, Genomics England | - | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 22, 2023 | This sequence change creates a premature translational stop signal (p.Tyr8231*) in the NEB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (rs754272530, gnomAD 0.006%). This premature translational stop signal has been observed in individual(s) with clinical features of nemaline myopathy (PMID: 29382405). This variant is also known as c.24588C>G (p.Tyr8196*). ClinVar contains an entry for this variant (Variation ID: 432817). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | Dec 03, 2018 | The heterozygous p.Tyr8196Ter variant in NEB was identified by our study in the compound heterozygous state, with a likely pathogenic variant, in one individual with nemaline myopathy. The presence of this variant in combination with a likely pathogenic variant and in an individual with nemaline myopathy increases the likelihood that the p.Tyr8196Ter variant is pathogenic. This variant has been identified in 0.005516% (5/90638) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs754272530). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. This nonsense variant leads to a premature termination codon at position 8196, which is predicted to lead to a truncated or absent protein. Loss of function of the NEB gene is an established disease mechanism for autosomal recessive nemaline myopathy. In summary, this variant meets criteria to be classified as pathogenic for nemaline myopathy an autosomal recessive manner based on the predicted impact of the variant and occurrence with a likely pathogenic in an individual with nemaline myopathy. ACMG/AMP Criteria applied: PM2, PVS1, PM3_Supporting (Richards 2015). - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 19, 2017 | The Y8231X pathogenic variant in the NEB gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The Y8231X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret Y8231X as a pathogenic variant. - |
Arthrogryposis multiplex congenita 6 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 26, 2023 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;D
Vest4
ClinPred
D
GERP RS
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AL_spliceai
Position offset: 8
Find out detailed SpliceAI scores and Pangolin per-transcript scores at