chr11-14878265-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_024514.5(CYP2R1):c.1363C>T(p.Arg455Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000291 in 1,612,770 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R455Q) has been classified as Uncertain significance.
Frequency
Consequence
NM_024514.5 missense
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/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP2R1 | NM_024514.5 | c.1363C>T | p.Arg455Trp | missense_variant | 5/5 | ENST00000334636.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP2R1 | ENST00000334636.10 | c.1363C>T | p.Arg455Trp | missense_variant | 5/5 | 1 | NM_024514.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000526 AC: 8AN: 151994Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000639 AC: 16AN: 250308Hom.: 1 AF XY: 0.0000739 AC XY: 10AN XY: 135340
GnomAD4 exome AF: 0.0000267 AC: 39AN: 1460776Hom.: 1 Cov.: 31 AF XY: 0.0000303 AC XY: 22AN XY: 726670
GnomAD4 genome AF: 0.0000526 AC: 8AN: 151994Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74240
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 21, 2023 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 455 of the CYP2R1 protein (p.Arg455Trp). This variant is present in population databases (rs146366698, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with CYP2R1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1385510). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects CYP2R1 function (PMID: 32115644). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at