rs281864922
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000824.5(GLRB):c.610+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000813 in 1,524,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000824.5 splice_donor_5th_base, intron
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 |
---|---|---|---|---|---|---|---|
GLRB | NM_000824.5 | c.610+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000264428.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLRB | ENST00000264428.9 | c.610+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_000824.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152068Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000479 AC: 12AN: 250564Hom.: 0 AF XY: 0.0000812 AC XY: 11AN XY: 135444
GnomAD4 exome AF: 0.0000867 AC: 119AN: 1372912Hom.: 0 Cov.: 22 AF XY: 0.0000828 AC XY: 57AN XY: 688504
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152068Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74248
ClinVar
Submissions by phenotype
Hyperekplexia 2 Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 20, 2023 | This sequence change falls in intron 6 of the GLRB gene. It does not directly change the encoded amino acid sequence of the GLRB protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs281864922, gnomAD 0.009%). This variant has been observed in individuals with clinical features of hyperekplexia (PMID: 11929858, 32911248; Invitae). This variant is also known as IVS5+5G>A. ClinVar contains an entry for this variant (Variation ID: 16059). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 11929858). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | curation | GeneReviews | Oct 04, 2012 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 04, 2022 | Intronic +5 splice site variant in a gene for which loss of function is a known mechanism of disease, and splice predictors support a deleterious effect; This variant is associated with the following publications: (PMID: 11929858, 32911248) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at