6-32038342-A-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The ENST00000486063.5(CYP21A2):n.3A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,541,254 control chromosomes in the GnomAD database, including 276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.012 (31 hom., cov: 32)
  • Exomes 𝑓: 0.015 (245 hom.)
• Consequence: CYP21A2 ENST00000486063.5 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.191

Genes affected

CYP21A2 (HGNC:2600): (cytochrome P450 family 21 subfamily A member 2) This gene encodes a member of the cytochrome P450 superfamily of enzymes. The cytochrome P450 proteins are monooxygenases which catalyze many reactions involved in drug metabolism and synthesis of cholesterol, steroids and other lipids. This protein localizes to the endoplasmic reticulum and hydroxylates steroids at the 21 position. Its activity is required for the synthesis of steroid hormones including cortisol and aldosterone. Mutations in this gene cause congenital adrenal hyperplasia. A related pseudogene is located near this gene; gene conversion events involving the functional gene and the pseudogene are thought to account for many cases of steroid 21-hydroxylase deficiency. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0124 (1889/152228) while in subpopulation NFE AF= 0.0196 (1336/67996). AF 95% confidence interval is 0.0188. There are 31 homozygotes in gnomad4. There are 931 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000486063.5	n.3A>C		non_coding_transcript_exon_variant	1/8	3
CYP21A2	ENST00000466779.5	c.-81A>C		5_prime_UTR_variant, NMD_transcript_variant	1/6	5
CYP21A2	ENST00000478281.5			upstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1889 AN: 152110 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.00360

Gnomad AMI AF: 0.0351

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.0146 AC: 20311 AN: 1389026 Hom.: 245 Cov.: 30 AF XY: 0.0140 AC XY: 9563 AN XY: 685394

Gnomad4 AFR exome AF: 0.00213

Gnomad4 AMR exome AF: 0.00213

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.0000379

Gnomad4 FIN exome AF: 0.0281

Gnomad4 NFE exome AF: 0.0171

Gnomad4 OTH exome AF: 0.00973

GnomAD4 genome AF: 0.0124 AC: 1889 AN: 152228 Hom.: 31 Cov.: 32 AF XY: 0.0125 AC XY: 931 AN XY: 74438

Gnomad4 AFR AF: 0.00359

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0311

Gnomad4 NFE AF: 0.0196

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00574 Hom.: 1

Bravo AF: 0.0100

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

CYP21A2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 22, 2024

The CYP21A2 c.-81A>C variant is located in the 5' untranslated region. To our knowledge, this variant has not been reported in the literature. Its minor allele frequency is up to ~2.5% in a subpopulation of the gnomAD database. However, this population frequency data may not be reliable since the variant is located within a highly homologous sequence region, and current next-generation sequencing technology may not accurately assign sequencing reads from the gene and pseudogene (Mandelker et al. 2016. PubMed ID: 27228465). Due to limited functional and genetic evidence, the clinical significance of the c.-81A>C variant is currently uncertain. Of note, promoter variants in CYP21A2 have been reported to reduce transcriptional activities and therefore could be associated with mild disease (Zhang et al. 2009. PubMed ID: 18702679; Araújo et al. 2007. PubMed ID: 17666484). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.065
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs554941446; hg19: chr6-32006119; COSMIC: COSV64473163; COSMIC: COSV64473163;