rs797045736
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001164508.2(NEB):c.2211+5G>T variant causes a splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_001164508.2 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NEB | NM_001164507.2 | c.2211+5G>T | splice_region_variant, intron_variant | Intron 23 of 181 | ENST00000427231.7 | NP_001157979.2 | ||
NEB | NM_001164508.2 | c.2211+5G>T | splice_region_variant, intron_variant | Intron 23 of 181 | ENST00000397345.8 | NP_001157980.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NEB | ENST00000397345.8 | c.2211+5G>T | splice_region_variant, intron_variant | Intron 23 of 181 | 5 | NM_001164508.2 | ENSP00000380505.3 | |||
NEB | ENST00000427231.7 | c.2211+5G>T | splice_region_variant, intron_variant | Intron 23 of 181 | 5 | NM_001164507.2 | ENSP00000416578.2 | |||
NEB | ENST00000489048.1 | n.1110+5G>T | splice_region_variant, intron_variant | Intron 11 of 11 | 1 | |||||
NEB | ENST00000409198.5 | c.2211+5G>T | splice_region_variant, intron_variant | Intron 23 of 149 | 5 | ENSP00000386259.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 29
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152200Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74358
ClinVar
Submissions by phenotype
Nemaline myopathy 2 Pathogenic:1Uncertain:3
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This sequence change falls in intron 23 of the NEB gene. It does not directly change the encoded amino acid sequence of the NEB protein. It affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). 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: 211586). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the c.2211+5G nucleotide in the NEB gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 21724397; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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. -
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not specified Uncertain:1
Variant summary: NEB c.2211+5G>T alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Two predict the variant abolishes a 5' splicing donor site. Two predict the variant weakens a 5' donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 204702 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.2211+5G>T in individuals affected with Nemaline Myopathy 2 and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 211586). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Nemaline myopathy Uncertain:1
The c.2211+5G>T variant in NEB has not been previously reported in individuals with nemaline myopathy, but has been identified in 0.002% (1/55150) Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs797045736). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 211586) and has been interpreted a likely pathogenic by Genetic Services Laboratory (University of Chicago) and a variant of uncertain significance by Invitae, Counsyl, and Women's Health and Genetics/Laboratory Corporation of America. This variant is located in the 3’ splice region. Computational tools do suggest an impact to splicing. However, this information is not predictive enough to determine/rule out pathogenicity. Two additional likely pathogenic variants, predicted to induce the same splicing effect as this variant, have been reported in ClinVar as being associated with nemaline myopathy, supporting that the c.2211+5G>T variant may be pathogenic (Variation ID: 552030, 1466481). In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain. ACMG/AMP Criteria applied: PS1_supporting, PP3, PM2_supporting (Richards 2015). -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at