6-32041147-G-A

Variant names:

• chr6-32041147-G-A
• rs6447
• NM_000500.9:c.*13G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:3 B:3
• Conservation: PhyloP100: -0.598

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]

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]

ACMG classification

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 rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9	c.*13G>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000644719.2	NP_000491.4
TNXB	NM_001365276.2	c.*202C>T		downstream_gene_variant		ENST00000644971.2	NP_001352205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2	c.*13G>A		3_prime_UTR_variant	Exon 10 of 10		NM_000500.9	ENSP00000496625.1
TNXB	ENST00000644971.2	c.*202C>T		downstream_gene_variant			NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes AF: 0.0157 AC: 2380 AN: 151294 Hom.: 58 Cov.: 33

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

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.: 33 AF XY: 0.0171 AC XY: 12261 AN XY: 714970

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.: 58 Cov.: 33 AF XY: 0.0160 AC XY: 1186 AN XY: 73984

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.: 14

Bravo AF: 0.0173

Asia WGS AF: 0.0310 AC: 108 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:2 Uncertain:1 Benign:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM3_VeryStrong+PP4 -

Oct 30, 2023

Zotz-Klimas Genetics Lab, MVZ Zotz Klimas

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided Uncertain:1 Benign:1

Sep 18, 2024

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. This variant is located in a genomic region of low or unreliable sequencing quality, and therefore estimations of its population frequency are uninformative in assessment of variant pathogenicity. This variant has been seen in trans with other recessive pathogenic CYP21A2 variants in multiple individuals with classic 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, and has been previously reported by Athena Diagnostics at nucleotide 1501. -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

CYP21A2-related disorder Uncertain:1

Jun 15, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

-

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Other links and lift over

dbSNP: rs6447; hg19: chr6-32008924; COSMIC: COSV64478062; COSMIC: COSV64478062;