rs786205528
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2PP5BS2
The NM_000682.7(ADRA2B):c.664C>T(p.Arg222*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,182 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000682.7 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461182Hom.: 0 Cov.: 38 AF XY: 0.00000550 AC XY: 4AN XY: 726892
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
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not specified Uncertain:1
Variant summary: ADRA2B c.664C>T (p.Arg222X) 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, however current evidence is not sufficient to establish loss of function as a mechanism for disease. The variant was absent in 248014 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.664C>T has been reported in the literature in individuals affected with intellectual disability or neurodevelopmental disorders without strong evidence of causality (e.g. Abouelhoda_2016, Monies_2019, Al Abdi_2023). These reports do not provide unequivocal conclusions about association of the variant with ADRA2B-Related Disorders. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27124789, 31130284, 37644014, 27431290). ClinVar contains an entry for this variant (Variation ID: 191117). Based on the evidence outlined above, the variant was classified as uncertain significance. -
Epilepsy, familial adult myoclonic, 2 Uncertain:1
This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at