rs555445835
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001164507.2(NEB):βc.24527_24528delβ(p.Pro8176ArgfsTer4) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000255 in 1,607,988 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (β β ). Synonymous variant affecting the same amino acid position (i.e. P8176P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001164507.2 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.24527_24528del | p.Pro8176ArgfsTer4 | frameshift_variant | 174/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.24527_24528del | p.Pro8176ArgfsTer4 | frameshift_variant | 174/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.24527_24528del | p.Pro8176ArgfsTer4 | frameshift_variant | 174/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.24527_24528del | p.Pro8176ArgfsTer4 | frameshift_variant | 174/182 | 5 | NM_001164507.2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000834 AC: 2AN: 239838Hom.: 0 AF XY: 0.00000771 AC XY: 1AN XY: 129674
GnomAD4 exome AF: 0.0000268 AC: 39AN: 1455838Hom.: 0 AF XY: 0.0000180 AC XY: 13AN XY: 723392
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152150Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74320
ClinVar
Submissions by phenotype
Nemaline myopathy 2 Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Counsyl | May 16, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Apr 04, 2024 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 22, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | This sequence change creates a premature translational stop signal (p.Pro8211Argfs*4) 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 (rs555445835, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 24056153, 25205138). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as c.24527_24528delCT. ClinVar contains an entry for this variant (Variation ID: 265493). For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jun 23, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 24, 2022 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 24056153, 25205138, 33442022, 32528171) - |
Dysphagia;C0239234:Low-set ears;C0266623:Abnormality of the neck Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Knight Diagnostic Laboratories, Oregon Health and Sciences University | Sep 09, 2019 | - - |
Nemaline myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 07, 2019 | Variant summary: NEB c.24632_24633delCT (p.Pro8211ArgfsX4) (also known as c.24527_24528delCT) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation variant, c.25241T>G (p.Leu8414X), downstream of this position has been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8.4e-06 in 237000 control chromosomes (gnomAD). c.24632_24633delCT has been reported in the literature in multiple compound heterozygous individuals affected with Nemaline Myopathy 2 (Gajda 2013, Lehtokari 2014). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Arthrogryposis multiplex congenita 6 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 30, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at