rs754432887
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PP3_Strong
The NM_000497.4(CYP11B1):c.1280G>A(p.Arg427His) variant causes a missense change. The variant allele was found at a frequency of 0.0000229 in 1,614,142 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 Uncertain significance (★★).
Frequency
Consequence
NM_000497.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 4 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152248Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000437 AC: 11AN: 251488Hom.: 0 AF XY: 0.0000809 AC XY: 11AN XY: 135920
GnomAD4 exome AF: 0.0000239 AC: 35AN: 1461894Hom.: 0 Cov.: 34 AF XY: 0.0000371 AC XY: 27AN XY: 727248
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152248Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74386
ClinVar
Submissions by phenotype
not specified Uncertain:1
Variant summary: CYP11B1 c.1280G>A (p.Arg427His) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.4e-05 in 251488 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in CYP11B1 causing Congenital Adrenal Hyperplasia (4.4e-05 vs 0.002), allowing no conclusion about variant significance. c.1280G>A has been reported in the literature in at least one homozygous individual affected with Congenital Adrenal Hyperplasia (Abbaszadegan_2013). These data indicate that the variant may be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One ClinVar submitter has assessed the variant since 2014: the variant was classified as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -
Deficiency of steroid 11-beta-monooxygenase;C3838731:Glucocorticoid-remediable aldosteronism Uncertain:1
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not provided Uncertain:1
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Deficiency of steroid 11-beta-monooxygenase Uncertain:1
NM_000497.3(CYP11B1):c.1280G>A(R427H) is a missense variant classified as a variant of uncertain significance in the context of congenital adrenal hyperplasia, CYP11B1-related. R427H has been observed in cases with relevant disease (PMID: 23345044, 8964882). Functional assessments of this variant are not available in the literature. Internal structural analysis of the variant is supportive of pathogenicity. R427H has been observed in population frequency databases (gnomAD: SAS 0.04%). In summary, there is insufficient evidence to classify NM_000497.3(CYP11B1):c.1280G>A(R427H) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at