chr8-116847643-A-G
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_006265.3(RAD21):c.1753T>C(p.Cys585Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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_006265.3 missense
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RAD21 | NM_006265.3 | c.1753T>C | p.Cys585Arg | missense_variant | Exon 14 of 14 | ENST00000297338.7 | NP_006256.1 | |
LOC112268030 | XR_002956724.2 | n.761-1245A>G | intron_variant | Intron 2 of 2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 30
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Cornelia de Lange syndrome 4 Pathogenic:3Other:1
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This sequence change replaces cysteine with arginine at codon 585 of the RAD21 protein (p.Cys585Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with Cornelia de Lange syndrome (PMID: 22633399, 32193685; external communication). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 35460). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects RAD21 function (PMID: 22633399). For these reasons, this variant has been classified as Pathogenic. -
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not provided Pathogenic:1Uncertain:1
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Reported in a family with Cornelia de Lange syndrome; however, information about parental testing was not provided (PMID: 32193685); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22633399, 20301283, 24038889, 30716475, 23882154, 32687945, 32193685, 30125677, 25575569, 27882533) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at