chr2-151696637-G-A
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP7
The NM_001164507.2(NEB):c.1569C>T(p.Asp523=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,609,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000097 ( 0 hom. )
Consequence
NEB
NM_001164507.2 splice_region, synonymous
NM_001164507.2 splice_region, synonymous
Scores
2
Splicing: ADA: 0.001049
2
Clinical Significance
Conservation
PhyloP100: 1.82
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 Likely_benign. Variant got -1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.36).
BP7
Synonymous conserved (PhyloP=1.83 with no splicing effect.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| NEB | NM_001164507.2 | c.1569C>T | p.Asp523= | splice_region_variant, synonymous_variant | 17/182 | ENST00000427231.7 | |
| NEB | NM_001164508.2 | c.1569C>T | p.Asp523= | splice_region_variant, synonymous_variant | 17/182 | ENST00000397345.8 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NEB | ENST00000397345.8 | c.1569C>T | p.Asp523= | splice_region_variant, synonymous_variant | 17/182 | 5 | NM_001164508.2 | P5 | |
| NEB | ENST00000427231.7 | c.1569C>T | p.Asp523= | splice_region_variant, synonymous_variant | 17/182 | 5 | NM_001164507.2 | A2 | |
| NEB | ENST00000489048.1 | n.468C>T | splice_region_variant, non_coding_transcript_exon_variant | 5/12 | 1 | ||||
| NEB | ENST00000409198.5 | c.1569C>T | p.Asp523= | splice_region_variant, synonymous_variant | 17/150 | 5 |
Frequencies
GnomAD3 genomes 0.000197 AC: 30AN: 152166Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000197 AC: 49AN: 249134Hom.: 0 AF XY: 0.000222 AC XY: 30AN XY: 135148
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GnomAD4 exome AF: 0.0000967 AC: 141AN: 1457712Hom.: 0 Cov.: 30 AF XY: 0.0000869 AC XY: 63AN XY: 725340
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GnomAD4 genome 0.000197 AC: 30AN: 152284Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13AN XY: 74472
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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 | Oct 24, 2022 | This sequence change affects codon 523 of the NEB mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the NEB protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs200758495, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with NEB-related conditions. ClinVar contains an entry for this variant (Variation ID: 534081). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. 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
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at