rs6447

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000500.9(CYP21A2):c.*13G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0171 in 1,587,566 control chromosomes in the GnomAD database, including 685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.016 ( 58 hom., cov: 33)

Exomes 𝑓: 0.017 ( 627 hom. )

Consequence

CYP21A2
NM_000500.9 3_prime_UTR

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:3

Conservation

PhyloP100: -0.598

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:

TNXB (HGNC:11976): (tenascin XB) This gene encodes a member of the tenascin family of extracellular matrix glycoproteins. The tenascins have anti-adhesive effects, as opposed to fibronectin which is adhesive. This protein is thought to function in matrix maturation during wound healing, and its deficiency has been associated with the connective tissue disorder Ehlers-Danlos syndrome. This gene localizes to the major histocompatibility complex (MHC) class III region on chromosome 6. It is one of four genes in this cluster which have been duplicated. The duplicated copy of this gene is incomplete and is a pseudogene which is transcribed but does not encode a protein. The structure of this gene is unusual in that it overlaps the CREBL1 and CYP21A2 genes at its 5' and 3' ends, respectively. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

TNXB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0629 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP21A2	NM_000500.9 linkuse as main transcript	c.*13G>A		3_prime_UTR_variant	10/10	ENST00000644719.2	NP_000491.4
TNXB	NM_001365276.2 linkuse as main transcript			downstream_gene_variant		ENST00000644971.2	NP_001352205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 linkuse as main transcript	c.*13G>A		3_prime_UTR_variant	10/10		NM_000500.9	ENSP00000496625	P1
TNXB	ENST00000644971.2 linkuse as main transcript			downstream_gene_variant			NM_001365276.2	ENSP00000496448		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.0157

AC:

2380

AN:

151294

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00393

Gnomad AMI

AF:

0.0100

Gnomad AMR

AF:

0.0283

Gnomad ASJ

AF:

0.00659

Gnomad EAS

AF:

0.0692

Gnomad SAS

AF:

0.0162

Gnomad FIN

AF:

0.0198

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0160

Gnomad OTH

AF:

0.0168

GnomAD3 exomes

AF:

0.0253

AC:

5997

AN:

236776

Hom.:

131

AF XY:

0.0233

AC XY:

3028

AN XY:

129706

show subpopulations

Gnomad AFR exome

AF:

0.00277

Gnomad AMR exome

AF:

0.0593

Gnomad ASJ exome

AF:

0.00493

Gnomad EAS exome

AF:

0.0755

Gnomad SAS exome

AF:

0.0165

Gnomad FIN exome

AF:

0.0184

Gnomad NFE exome

AF:

0.0154

Gnomad OTH exome

AF:

0.0183

GnomAD4 exome

AF:

0.0173

AC:

24837

AN:

1436150

Hom.:

627

Cov.:

AF XY:

0.0171

AC XY:

12261

AN XY:

714970

show subpopulations

Gnomad4 AFR exome

AF:

0.00267

Gnomad4 AMR exome

AF:

0.0513

Gnomad4 ASJ exome

AF:

0.00581

Gnomad4 EAS exome

AF:

0.0625

Gnomad4 SAS exome

AF:

0.0164

Gnomad4 FIN exome

AF:

0.0193

Gnomad4 NFE exome

AF:

0.0152

Gnomad4 OTH exome

AF:

0.0148

GnomAD4 genome

AF:

0.0157

AC:

2378

AN:

151416

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1186

AN XY:

73984

show subpopulations

Gnomad4 AFR

AF:

0.00392

Gnomad4 AMR

AF:

0.0282

Gnomad4 ASJ

AF:

0.00659

Gnomad4 EAS

AF:

0.0688

Gnomad4 SAS

AF:

0.0164

Gnomad4 FIN

AF:

0.0198

Gnomad4 NFE

AF:

0.0160

Gnomad4 OTH

AF:

0.0171

Alfa

AF:

0.0108

Hom.:

Bravo

AF:

0.0173

Asia WGS

AF:

0.0310

AC:

108

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Pathogenic:1Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Pathogenic, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Oct 30, 2023	- -

not provided

Uncertain:1Benign:1

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 27, 2023	Available data are insufficient to determine the clinical significance of the variant at this time. Frequency data for this variant in the general population cannot be distinguished from that of the CYP21P pseudogene, and are therefore uninformative in assessment of variant pathogenicity (http://gnomad.broadinstitute.org). This variant has been seen in trans with other recessive pathogenic CYP21A2 variants in multiple individuals with congenital and also nonclassic forms of CAH. Assessment of experimental evidence regarding the effect of this variant on protein function is inconclusive. Results from PMID: 21521936 show a reduction in mRNA levels due to this variant, however, neither protein levels nor protein activity were assayed. This variant is also referred to by nucleotide 4397 in some published literature. -

CYP21A2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2024

The CYP21A2 c.*13G>A variant is located in the 3' untranslated region. This particular variant has been previously reported to be associated with a mild form of congenital adrenal hyperplasia (CAH) (Menabò et al. 2012. PubMed ID: 21521936). Its minor allele frequency is up to ~7.5% in East Asian individuals. However, this minor allele frequency is based on the current next-generation sequencing technology and may not be an accurate estimate because this variant is located within a highly homologous sequence region (Mandelker et al. 2016. PubMed ID: 27228465). Due to limited functional and genetic evidence, the clinical significance of the c.*13G>A variant is currently uncertain. -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

2.1

DANN

Benign

0.64

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