rs773952935
Variant summary
Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1_ModeratePM2PP3PP5_Very_Strong
The NM_001164507.2(NEB):c.294+2T>C variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000683 in 1,609,464 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_001164507.2 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.294+2T>C | splice_donor_variant | ENST00000427231.7 | |||
NEB | NM_001164508.2 | c.294+2T>C | splice_donor_variant | ENST00000397345.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.294+2T>C | splice_donor_variant | 5 | NM_001164508.2 | P5 | |||
NEB | ENST00000427231.7 | c.294+2T>C | splice_donor_variant | 5 | NM_001164507.2 | A2 | |||
NEB | ENST00000409198.5 | c.294+2T>C | splice_donor_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000404 AC: 10AN: 247568Hom.: 0 AF XY: 0.0000372 AC XY: 5AN XY: 134360
GnomAD4 exome AF: 0.00000686 AC: 10AN: 1457244Hom.: 0 Cov.: 31 AF XY: 0.00000691 AC XY: 5AN XY: 724052
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74366
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | May 25, 2016 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 27, 2023 | Canonical splice site variant expected to result in aberrant splicing, although in the absence of functional evidence the actual effect of this sequence change is unknown.; Deletions involving coding exons of this gene are a known mechanism of disease (HGMD); This variant is associated with the following publications: (PMID: 16917880, 25525159, 25205138) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 31, 2023 | - - |
Nemaline myopathy 2 Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 23, 2023 | This sequence change affects a donor splice site in intron 5 of the NEB gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NEB are known to be pathogenic (PMID: 25205138). This variant is present in population databases (rs773952935, gnomAD 0.03%). Disruption of this splice site has been observed in individual(s) with nemaline myopathy (PMID: 16917880). 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 g.5468T>C. ClinVar contains an entry for this variant (Variation ID: 287422). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Counsyl | May 19, 2017 | - - |
Nemaline myopathy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 29, 2019 | Variant summary: NEB c.294+2T>C is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: four predict the variant abolishes a 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-05 in 247568 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NEB causing Nemaline Myopathy 2 (4e-05 vs 0.0035), allowing no conclusion about variant significance. c.294+2T>C has been reported in the literature in a compound heterozygous individual affected with Nemaline Myopathy 2, who carried another pathogenic variant in trans (Lehtokari 2006). Another variant affecting the same canonical splice donor site (c.294+1G>A) was reported in the same study to result in an in-frame skipping of exon 5 with the deletion of 72 amino acids (i.e. p.Thr27_Pro98del; based on cDNA sequence analysis of mRNA isolated from patient muscle biopsy sample); therefore it was predicted that the variant of interest would cause a similar splicing defect (Lehtokari 2006). Three ClinVar submission from clinical diagnostic laboratories (evaluation after 2014) cite the variant twice as likely pathogenic and once as 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 | Feb 22, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at