chr2-151519759-G-A
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001164507.2(NEB):c.22489C>T(p.Arg7497Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,604,630 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R7497R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001164507.2 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
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.22489C>T | p.Arg7497Ter | stop_gained | 154/182 | ENST00000427231.7 | |
NEB | NM_001164508.2 | c.22489C>T | p.Arg7497Ter | stop_gained | 154/182 | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.22489C>T | p.Arg7497Ter | stop_gained | 154/182 | 5 | NM_001164508.2 | P5 | |
NEB | ENST00000427231.7 | c.22489C>T | p.Arg7497Ter | stop_gained | 154/182 | 5 | NM_001164507.2 | A2 |
Frequencies
GnomAD3 genomes AF: 0.00000659 AC: 1AN: 151718Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000804 AC: 2AN: 248744Hom.: 0 AF XY: 0.0000148 AC XY: 2AN XY: 134964
GnomAD4 exome AF: 0.00000413 AC: 6AN: 1452912Hom.: 0 Cov.: 29 AF XY: 0.00000829 AC XY: 6AN XY: 723392
GnomAD4 genome AF: 0.00000659 AC: 1AN: 151718Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74066
ClinVar
Submissions by phenotype
not provided Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2023 | Identified in a patient with the typical form of nemaline myopathy, although additional clinical information was not included (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 significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 31589614, 25205138) - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Sep 27, 2022 | The NEB c.22489C>T (p.Arg7497Ter) nonsense variant results in the substitution of arginine at amino acid position 7497 with a stop codon. Loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay is expected. This variant, also referred to as c.22594C>T (p.Arg7532Ter), has been reported in one individual with nemaline myopathy (PMID: 25205138). This variant is reported in the Genome Aggregation Database in two alleles at a frequency of 0.000008 in the Total population (version 2.1.1). Based on the available evidence, the c.22489C>T (p.Arg7497Ter) variant is classified as pathogenic for nemaline myopathy. - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Nov 21, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Jul 09, 2018 | DNA sequence analysis of the NEB gene demonstrated a sequence change, c.17386C>T, which results in the creation of a premature stop codon at amino acid position 5796, p.Arg5796*. This sequence change is predicted to result in an abnormal transcript, which may be degraded, or may lead to the production of a truncated NEB protein with potentially abnormal function. - |
Nemaline myopathy 2 Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Feb 13, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 02, 2023 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 556650). This variant is also known as p.Arg7497*. This premature translational stop signal has been observed in individual(s) with NEB-related conditions (PMID: 25205138). This variant is present in population databases (rs760935667, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Arg7532*) 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). - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Nemaline myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 08, 2023 | Variant summary: NEB c.22594C>T (p.Arg7532X) 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. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 8e-06 in 248744 control chromosomes (gnomAD). he variant, c.22594C>T, has been reported in the literature in individuals affected with Nemaline Myopathy 2 (Lehtokari_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Arthrogryposis multiplex congenita 6 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 21, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at