6-32038481-G-A
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000500.9(CYP21A2):c.59G>A(p.Trp20*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,204 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 Pathogenic (★).
Frequency
Consequence
NM_000500.9 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CYP21A2 | NM_000500.9 | c.59G>A | p.Trp20* | stop_gained | Exon 1 of 10 | ENST00000644719.2 | NP_000491.4 | |
CYP21A2 | NM_001128590.4 | c.59G>A | p.Trp20* | stop_gained | Exon 1 of 9 | NP_001122062.3 | ||
CYP21A2 | NM_001368143.2 | c.-366G>A | 5_prime_UTR_variant | Exon 1 of 10 | NP_001355072.1 | |||
CYP21A2 | NM_001368144.2 | c.-276G>A | 5_prime_UTR_variant | Exon 1 of 9 | NP_001355073.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00000658 AC: 1AN: 152086Hom.: 0 Cov.: 32
GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000279 AC: 4AN: 1434534Hom.: 0 Cov.: 105 AF XY: 0.00000281 AC XY: 2AN XY: 711408
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74404
ClinVar
Submissions by phenotype
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:1
Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (MIM#201910) and nonclassic type hyperandrogenism due to 21-hydroxylase deficiency (MIM#201910). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is located within the first 102 nucleotides of the coding sequence and is predicted to escape nonsense-mediated decay). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: c.59G>A with 1 heterozygote, 0 homozygotes; c.60G>A with 3 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This nucleotide change and c.60G>A, both predicted to result in p.(Trp20*), have been reported in multiple unrelated individuals with congenital adrenal hyperplasia (PMIDs: 27185867, 30048636, 30816000), and have been reported as pathogenic by a clinical laboratory (ClinVar). Both nucleotide changes have been listed as pathogenic in the EMQN guideline for molecular genetic testing and reporting of 21-hydroxylase deficiency (PMID: 32616876). c.59G>A has also been reported as in cis with p.(Val282Leu) although that is uncommon (PMID: 27185867). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at