2-151727801-ATGCTGGCTGTGCCAG-ATGCTGGCTGTGCCAGTGCTGGCTGTGCCAG
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP3
The NM_001164508.2(NEB):c.169_183dupCTGGCACAGCCAGCA(p.Ala61_Ser62insLeuAlaGlnProAla) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00014 in 1,612,006 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00014 ( 0 hom. )
Consequence
NEB
NM_001164508.2 conservative_inframe_insertion
NM_001164508.2 conservative_inframe_insertion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -0.579
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;
BP3
Nonframeshift variant in repetitive region in NM_001164508.2
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| NEB | NM_001164507.2 | c.169_183dupCTGGCACAGCCAGCA | p.Ala61_Ser62insLeuAlaGlnProAla | conservative_inframe_insertion | 5/182 | ENST00000427231.7 | NP_001157979.2 | |
| NEB | NM_001164508.2 | c.169_183dupCTGGCACAGCCAGCA | p.Ala61_Ser62insLeuAlaGlnProAla | conservative_inframe_insertion | 5/182 | ENST00000397345.8 | NP_001157980.2 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| NEB | ENST00000397345.8 | c.169_183dupCTGGCACAGCCAGCA | p.Ala61_Ser62insLeuAlaGlnProAla | conservative_inframe_insertion | 5/182 | 5 | NM_001164508.2 | ENSP00000380505.3 | ||
| NEB | ENST00000427231.7 | c.169_183dupCTGGCACAGCCAGCA | p.Ala61_Ser62insLeuAlaGlnProAla | conservative_inframe_insertion | 5/182 | 5 | NM_001164507.2 | ENSP00000416578.2 | ||
| NEB | ENST00000409198.5 | c.169_183dupCTGGCACAGCCAGCA | p.Ala61_Ser62insLeuAlaGlnProAla | conservative_inframe_insertion | 5/150 | 5 | ENSP00000386259.1 |
Frequencies
GnomAD3 genomes 0.000105 AC: 16AN: 152048Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000145 AC: 36AN: 248352Hom.: 0 AF XY: 0.000163 AC XY: 22AN XY: 134632
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GnomAD4 exome AF: 0.000144 AC: 210AN: 1459840Hom.: 0 Cov.: 31 AF XY: 0.000140 AC XY: 102AN XY: 726092
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GnomAD4 genome 0.000105 AC: 16AN: 152166Hom.: 0 Cov.: 32 AF XY: 0.0000941 AC XY: 7AN XY: 74400
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:5Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Nemaline myopathy 2 Uncertain:2
| Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 17, 2020 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 15, 2022 | This variant, c.169_183dup, results in the insertion of 5 amino acid(s) of the NEB protein (p.Leu57_Ala61dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs770886969, 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: 421412). Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
not provided Uncertain:1Benign:1
| Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2023 | NEB: PM4, BP4 - |
| Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 22, 2019 | This variant is associated with the following publications: (PMID: 32222963) - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 15, 2024 | Variant summary: NEB c.169_183dup15 (p.Leu57_Ala61dup) results in an in-frame duplication that is predicted to duplicate 5 amino acids into the encoded protein. The variant allele was found at a frequency of 0.00014 in 248352 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in NEB causing Nemaline Myopathy 2 (0.00014 vs 0.0035), allowing no conclusion about variant significance. c.169_183dup15 has been reported in the literature in compound heterozygous individuals affected with Nemaline Myopathy 2 or Multiple Congenital Contractures (Wang_2020, Turgut_2024)). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 38278647, 32222963). ClinVar contains an entry for this variant (Variation ID: 421412). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Arthrogryposis multiplex congenita 6 Uncertain:1
| Uncertain significance, no assertion criteria provided | clinical testing | Istanbul Faculty of Medicine, Istanbul University | Jan 10, 2022 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at