6-32041507-G-A

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.*373G>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 0.0201 in 1,215,108 control chromosomes in the GnomAD database, including 2,328 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.054 (786 hom., cov: 24)
  • Exomes 𝑓: 0.015 (1542 hom.)
• Consequence: CYP21A2 NM_000500.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.87

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 6-32041507-G-A is Benign according to our data. Variant chr6-32041507-G-A is described in ClinVar as [Benign]. Clinvar id is 1264810.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.*373G>A		3_prime_UTR_variant	10/10	ENST00000644719.2
TNXB	NM_001365276.2	c.12634-57C>T		intron_variant		ENST00000644971.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.*373G>A		3_prime_UTR_variant	10/10		NM_000500.9	P1
TNXB	ENST00000644971.2	c.12634-57C>T		intron_variant			NM_001365276.2

Frequencies

GnomAD3 genomes AF: 0.0544 AC: 7840 AN: 144206 Hom.: 785 Cov.: 24

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.0306

Gnomad AMR AF: 0.0517

Gnomad ASJ AF: 0.0157

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00210

Gnomad FIN AF: 0.00261

Gnomad MID AF: 0.0362

Gnomad NFE AF: 0.0422

Gnomad OTH AF: 0.0540

GnomAD4 exome AF: 0.0155 AC: 16546 AN: 1070774 Hom.: 1542 Cov.: 17 AF XY: 0.0149 AC XY: 8071 AN XY: 540436

Gnomad4 AFR exome AF: 0.0668

Gnomad4 AMR exome AF: 0.0267

Gnomad4 ASJ exome AF: 0.00978

Gnomad4 EAS exome AF: 0.0000289

Gnomad4 SAS exome AF: 0.000775

Gnomad4 FIN exome AF: 0.00418

Gnomad4 NFE exome AF: 0.0160

Gnomad4 OTH exome AF: 0.0238

GnomAD4 genome AF: 0.0544 AC: 7848 AN: 144334 Hom.: 786 Cov.: 24 AF XY: 0.0512 AC XY: 3601 AN XY: 70386

Gnomad4 AFR AF: 0.110

Gnomad4 AMR AF: 0.0517

Gnomad4 ASJ AF: 0.0157

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00186

Gnomad4 FIN AF: 0.00261

Gnomad4 NFE AF: 0.0422

Gnomad4 OTH AF: 0.0534

Alfa AF: 0.00817 Hom.: 12

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	0.35
Dann	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs451652; hg19: chr6-32009284; COSMIC: COSV64486345; COSMIC: COSV64486345;