Variant 6-32038342-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

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 (no stars).

Frequency

Genomes: 𝑓 0.012 ( 31 hom., cov: 32)

Exomes 𝑓: 0.015 ( 245 hom. )

Consequence

CYP21A2
ENST00000486063.5 non_coding_transcript_exon

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: -0.191

Variant links:

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]

CYP21A2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 GnomAd4 at 31 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

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

Frequencies

GnomAD3 genomes

AF:

0.0124

AC:

1889

AN:

152110

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.0140

AC XY:

9563

AN XY:

685394

show subpopulations

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.:

Cov.:

AF XY:

0.0125

AC XY:

931

AN XY:

74438

show subpopulations

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.:

Bravo

AF:

0.0100

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CYP21A2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over