rs200731870
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001164507.2(NEB):c.25336C>T(p.Arg8446Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,613,188 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R8446R) has been classified as Likely benign.
Frequency
Consequence
NM_001164507.2 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.25336C>T | p.Arg8446Ter | stop_gained | 181/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.25336C>T | p.Arg8446Ter | stop_gained | 181/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.25336C>T | p.Arg8446Ter | stop_gained | 181/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.25336C>T | p.Arg8446Ter | stop_gained | 181/182 | 5 | NM_001164507.2 | A2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152094Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000322 AC: 8AN: 248620Hom.: 0 AF XY: 0.0000371 AC XY: 5AN XY: 134826
GnomAD4 exome AF: 0.0000260 AC: 38AN: 1461094Hom.: 0 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 726836
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152094Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4AN XY: 74288
ClinVar
Submissions by phenotype
Nemaline myopathy 2 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 15, 2024 | This sequence change creates a premature translational stop signal (p.Arg8481*) 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 (rs200731870, gnomAD 0.005%). This premature translational stop signal has been observed in individual(s) with nemaline myopathy (PMID: 25205138). ClinVar contains an entry for this variant (Variation ID: 449500). For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | Feb 02, 2017 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 30, 2022 | Reported in a family with nemaline myopathy who also harbored a NEB frameshift variant, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (Lehtokari et al., 2014); Nonsense 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 a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30467404, 25205138, 30057997, 34426522, 31589614, 31127727) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 18, 2019 | - - |
Nemaline myopathy Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 13, 2020 | Variant summary: NEB c.25441C>T (p.Arg8481X) 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. The variant allele was found at a frequency of 3.2e-05 in 248620 control chromosomes. c.25441C>T has been reported in the literature in at-least two individuals affected with Nemaline Myopathy (Lehtokari_2014) and congenital core-rod myopathy (Wunderlich_2018) respectively. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic (n=2)/likely pathogenic (n=1). 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 | Feb 22, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at