rs994764994
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP3_StrongPP5
The NM_000500.9(CYP21A2):āc.922T>Gā(p.Leu308Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,544 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000500.9 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP21A2 | NM_000500.9 | c.922T>G | p.Leu308Val | missense_variant | 7/10 | ENST00000644719.2 | |
CYP21A2 | NM_001128590.4 | c.832T>G | p.Leu278Val | missense_variant | 6/9 | ||
CYP21A2 | NM_001368143.2 | c.517T>G | p.Leu173Val | missense_variant | 7/10 | ||
CYP21A2 | NM_001368144.2 | c.517T>G | p.Leu173Val | missense_variant | 6/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP21A2 | ENST00000644719.2 | c.922T>G | p.Leu308Val | missense_variant | 7/10 | NM_000500.9 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.0000162 AC: 4AN: 246400Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 134266
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460544Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0AN XY: 726596
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 14, 2018 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 13, 2023 | Variant summary: CYP21A2 c.922T>G (p.Leu308Val) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.6e-05 in 246400 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.922T>G has been reported in the literature in individuals affected with Congenital Adrenal Hyperplasia (CAH), including at least one individual with simple virilizing CAH (e.g., Sarafoglou_Pediatrics_2012, Sarafoglou_JAMA_2012) and at least two individuals with non-classic CAH (e.g., New_2013, Bruque_2013, Wan_2023). 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. The following publications have been ascertained in the context of this evaluation (PMID: 27966633, 23359698, 23071209, 36167262, 22692165). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at