rs757608533
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_000500.9(CYP21A2):c.49C>T(p.Arg17Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000197 in 1,575,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign 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. R17L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000500.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP21A2 | NM_000500.9 | c.49C>T | p.Arg17Cys | missense_variant | 1/10 | ENST00000644719.2 | |
CYP21A2 | NM_001128590.4 | c.49C>T | p.Arg17Cys | missense_variant | 1/9 | ||
CYP21A2 | NM_001368143.2 | c.-376C>T | 5_prime_UTR_variant | 1/10 | |||
CYP21A2 | NM_001368144.2 | c.-286C>T | 5_prime_UTR_variant | 1/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP21A2 | ENST00000644719.2 | c.49C>T | p.Arg17Cys | missense_variant | 1/10 | NM_000500.9 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000107 AC: 2AN: 186390Hom.: 0 AF XY: 0.0000196 AC XY: 2AN XY: 101786
GnomAD4 exome AF: 0.0000204 AC: 29AN: 1423264Hom.: 0 Cov.: 103 AF XY: 0.0000213 AC XY: 15AN XY: 704810
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152134Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74310
ClinVar
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 25, 2023 | Variant summary: CYP21A2 c.49C>T (p.Arg17Cys) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.1e-05 in 186390 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.49C>T has been reported in the literature as a heterozygous genotype in at-least one individual with a suspicion of Congenital Adrenal Hyperplasia (example, de Paula_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Congenital Adrenal Hyperplasia. At least one publication reports experimental evidence evaluating an impact on protein function (de Paula_2016). The most pronounced variant effect results in >80%-90% of normal CYP21A2 activity in vitro. The following publications have been ascertained in the context of this evaluation (PMID: 32616876, 27721825). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense c.49C>T p.Arg17Cys variant in the CYP21A2 gene has been reported in heterozygous carriers and it demonstrated a very mild reduction in enzyme activity, de Paula Michelatto, Débora et al.,2016. This variant is reported with the allele frequency 0.001% in the gnomAD Exomes and novel in 1000 Genomes. It is submitted to ClinVar as Uncertain Significance. The amino acid Arginine at position 17 is changed to a Cystine changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Arg17Cys in CYP21A2 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 21, 2018 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at