6-32041502-T-C

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.*368T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 1,163,640 control chromosomes in the GnomAD database, including 2,993 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.061 (805 hom., cov: 24)
  • Exomes 𝑓: 0.017 (2188 hom.)
• Consequence: CYP21A2 NM_000500.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.20

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 6-32041502-T-C is Benign according to our data. Variant chr6-32041502-T-C is described in ClinVar as [Benign]. Clinvar id is 1231280.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32041502-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.*368T>C		3_prime_UTR_variant	10/10	ENST00000644719.2
TNXB	NM_001365276.2	c.12634-52A>G		intron_variant		ENST00000644971.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.*368T>C		3_prime_UTR_variant	10/10		NM_000500.9	P1
TNXB	ENST00000644971.2	c.12634-52A>G		intron_variant			NM_001365276.2

Frequencies

GnomAD3 genomes AF: 0.0607 AC: 8131 AN: 133864 Hom.: 803 Cov.: 24

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.0578

Gnomad ASJ AF: 0.0179

Gnomad EAS AF: 0.00650

Gnomad SAS AF: 0.00495

Gnomad FIN AF: 0.00555

Gnomad MID AF: 0.0401

Gnomad NFE AF: 0.0466

Gnomad OTH AF: 0.0591

GnomAD3 exomes AF: 0.0214 AC: 3157 AN: 147832 Hom.: 495 AF XY: 0.0197 AC XY: 1559 AN XY: 78976

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.00354

Gnomad EAS exome AF: 0.00379

Gnomad SAS exome AF: 0.00256

Gnomad FIN exome AF: 0.00212

Gnomad NFE exome AF: 0.0282

Gnomad OTH exome AF: 0.0308

GnomAD4 exome AF: 0.0174 AC: 17947 AN: 1029648 Hom.: 2188 Cov.: 17 AF XY: 0.0171 AC XY: 8883 AN XY: 520218

Gnomad4 AFR exome AF: 0.0733

Gnomad4 AMR exome AF: 0.0283

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.00704

Gnomad4 SAS exome AF: 0.00692

Gnomad4 FIN exome AF: 0.00662

Gnomad4 NFE exome AF: 0.0172

Gnomad4 OTH exome AF: 0.0269

GnomAD4 genome AF: 0.0608 AC: 8143 AN: 133992 Hom.: 805 Cov.: 24 AF XY: 0.0571 AC XY: 3732 AN XY: 65318

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0579

Gnomad4 ASJ AF: 0.0179

Gnomad4 EAS AF: 0.00652

Gnomad4 SAS AF: 0.00468

Gnomad4 FIN AF: 0.00555

Gnomad4 NFE AF: 0.0466

Gnomad4 OTH AF: 0.0589

Alfa AF: 0.0443 Hom.: 136

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	1.5
Dann	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs415620; hg19: chr6-32009279; COSMIC: COSV64486341; COSMIC: COSV64486341;