6-32038350-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The ENST00000486063.5(CYP21A2):n.11C>T 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 0.000666 in 1,542,942 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00055 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (8 hom.)
• Consequence: CYP21A2 ENST00000486063.5 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00200

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BS2: High Homozygotes in GnomAd at 2 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.11C>T		non_coding_transcript_exon_variant	1/8	3
CYP21A2	ENST00000466779.5	c.-73C>T		5_prime_UTR_variant, NMD_transcript_variant	1/6	5
CYP21A2	ENST00000478281.5			upstream_gene_variant		4

Frequencies

GnomAD3 genomes AF: 0.000552 AC: 84 AN: 152126 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000662

Gnomad OTH AF: 0.00144

GnomAD4 exome AF: 0.000679 AC: 944 AN: 1390698 Hom.: 8 Cov.: 30 AF XY: 0.000736 AC XY: 505 AN XY: 686222

Gnomad4 AFR exome AF: 0.00305

Gnomad4 AMR exome AF: 0.000168

Gnomad4 ASJ exome AF: 0.000795

Gnomad4 EAS exome AF: 0.0000840

Gnomad4 SAS exome AF: 0.00178

Gnomad4 FIN exome AF: 0.000139

Gnomad4 NFE exome AF: 0.000511

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.000552 AC: 84 AN: 152244 Hom.: 2 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74446

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000662

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000344 Hom.: 0

Bravo AF: 0.000638

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

Oct 21, 2022

The CYP21A2 c.-73C>T variant is located in the 5' untranslated region. This variant has been reported in an individual with polycystic ovary syndrome (Polat et al. 2019. PubMed ID: 30811025). This variant is reported in 0.12% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-32006127-C-T). However, this minor allele frequency may not be an accurate estimate because this variant is located within a highly homologous sequence region (Mandelker et al. 2016. PubMed ID: 27228465). Of note, promoter variants in CYP21A2 have been reported to reduce transcriptional activities and therefore possibly associated to milder disease expressivity (Zhang et al. 2009. PubMed ID: 18702679; Araújo et al. 2007. PubMed ID: 17666484). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	2.4
Dann	Benign	0.85

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: rs186349245; hg19: chr6-32006127;