rs121918368
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5
The NM_016302.4(CRBN):c.1255C>T(p.Arg419Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,613,808 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_016302.4 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CRBN | NM_016302.4 | c.1255C>T | p.Arg419Ter | stop_gained | 11/11 | ENST00000231948.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CRBN | ENST00000231948.9 | c.1255C>T | p.Arg419Ter | stop_gained | 11/11 | 1 | NM_016302.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152108Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251270Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135802
GnomAD4 exome AF: 0.00000479 AC: 7AN: 1461700Hom.: 0 Cov.: 33 AF XY: 0.00000413 AC XY: 3AN XY: 727142
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152108Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74290
ClinVar
Submissions by phenotype
not provided Pathogenic:2Uncertain:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Apr 01, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 14, 2023 | ClinVar contains an entry for this variant (Variation ID: 1821). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this premature translational stop signal affects CRBN function (PMID: 23983124, 24993823). 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. This premature translational stop signal has been observed in individual(s) with intellectual disability (PMID: 15557513). It has also been observed to segregate with disease in related individuals. This sequence change creates a premature translational stop signal (p.Arg419*) in the CRBN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 24 amino acid(s) of the CRBN protein. This variant is present in population databases (rs121918368, gnomAD 0.007%). - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 11, 2023 | Published functional studies demonstrate the variant results in impaired protein function (PMID: 23983124, 24993823); Nonsense variant predicted to result in protein truncation as the last 24 amino acids are lost, although loss-of-function variants have not been reported downstream of this position in the protein; This variant is associated with the following publications: (PMID: 23983124, 24993823, 15557513) - |
Intellectual disability, autosomal recessive 2 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 11, 2013 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at