6-32041524-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000500.9(CYP21A2):c.*390A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,150,876 control chromosomes in the GnomAD database, including 1,112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.049 (576 hom., cov: 24)
  • Exomes 𝑓: 0.013 (536 hom.)
• Consequence: CYP21A2 NM_000500.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0580

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-32041524-A-G is Benign according to our data. Variant chr6-32041524-A-G is described in ClinVar as [Benign]. Clinvar id is 1183188.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32041524-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.*390A>G		3_prime_UTR_variant	10/10	ENST00000644719.2
TNXB	NM_001365276.2	c.12634-74T>C		intron_variant		ENST00000644971.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.*390A>G		3_prime_UTR_variant	10/10		NM_000500.9	P1
TNXB	ENST00000644971.2	c.12634-74T>C		intron_variant			NM_001365276.2

Frequencies

GnomAD3 genomes AF: 0.0493 AC: 7117 AN: 144322 Hom.: 569 Cov.: 24

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0544

Gnomad ASJ AF: 0.0995

Gnomad EAS AF: 0.00704

Gnomad SAS AF: 0.00678

Gnomad FIN AF: 0.00144

Gnomad MID AF: 0.0325

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0657

GnomAD4 exome AF: 0.0129 AC: 12950 AN: 1006428 Hom.: 536 Cov.: 15 AF XY: 0.0123 AC XY: 6309 AN XY: 511274

Gnomad4 AFR exome AF: 0.0974

Gnomad4 AMR exome AF: 0.0337

Gnomad4 ASJ exome AF: 0.0702

Gnomad4 EAS exome AF: 0.00483

Gnomad4 SAS exome AF: 0.00515

Gnomad4 FIN exome AF: 0.00192

Gnomad4 NFE exome AF: 0.00895

Gnomad4 OTH exome AF: 0.0248

GnomAD4 genome AF: 0.0495 AC: 7149 AN: 144448 Hom.: 576 Cov.: 24 AF XY: 0.0463 AC XY: 3265 AN XY: 70472

Gnomad4 AFR AF: 0.125

Gnomad4 AMR AF: 0.0544

Gnomad4 ASJ AF: 0.0995

Gnomad4 EAS AF: 0.00705

Gnomad4 SAS AF: 0.00699

Gnomad4 FIN AF: 0.00144

Gnomad4 NFE AF: 0.0168

Gnomad4 OTH AF: 0.0664

Alfa AF: 0.0425 Hom.: 70

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	3.6
Dann	Benign	0.66

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: rs7774739; hg19: chr6-32009301;