6-32041577-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000500.9(CYP21A2):c.*443T>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 0.0105 in 1,047,538 control chromosomes in the GnomAD database, including 167 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (49 hom., cov: 24)
  • Exomes 𝑓: 0.0089 (118 hom.)
• Consequence: CYP21A2 NM_000500.9 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.00

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=-0.93).
• BP6: Variant 6-32041577-T-C is Benign according to our data. Variant chr6-32041577-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 1194012.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32041577-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0202 (2967/147138) while in subpopulation AMR AF= 0.0397 (594/14966). AF 95% confidence interval is 0.037. There are 49 homozygotes in gnomad4. There are 1331 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 49 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.*443T>C		3_prime_UTR_variant	10/10	ENST00000644719.2
TNXB	NM_001365276.2	c.12634-127A>G		intron_variant		ENST00000644971.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.*443T>C		3_prime_UTR_variant	10/10		NM_000500.9	P1
TNXB	ENST00000644971.2	c.12634-127A>G		intron_variant			NM_001365276.2

Frequencies

GnomAD3 genomes AF: 0.0202 AC: 2964 AN: 147014 Hom.: 49 Cov.: 24

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.00112

Gnomad AMR AF: 0.0397

Gnomad ASJ AF: 0.0912

Gnomad EAS AF: 0.00329

Gnomad SAS AF: 0.00178

Gnomad FIN AF: 0.00105

Gnomad MID AF: 0.0227

Gnomad NFE AF: 0.0142

Gnomad OTH AF: 0.0432

GnomAD4 exome AF: 0.00889 AC: 8002 AN: 900400 Hom.: 118 Cov.: 13 AF XY: 0.00855 AC XY: 3946 AN XY: 461474

Gnomad4 AFR exome AF: 0.0204

Gnomad4 AMR exome AF: 0.0256

Gnomad4 ASJ exome AF: 0.0567

Gnomad4 EAS exome AF: 0.00113

Gnomad4 SAS exome AF: 0.00135

Gnomad4 FIN exome AF: 0.00168

Gnomad4 NFE exome AF: 0.00715

Gnomad4 OTH exome AF: 0.0172

GnomAD4 genome AF: 0.0202 AC: 2967 AN: 147138 Hom.: 49 Cov.: 24 AF XY: 0.0185 AC XY: 1331 AN XY: 71834

Gnomad4 AFR AF: 0.0255

Gnomad4 AMR AF: 0.0397

Gnomad4 ASJ AF: 0.0912

Gnomad4 EAS AF: 0.00330

Gnomad4 SAS AF: 0.00178

Gnomad4 FIN AF: 0.00105

Gnomad4 NFE AF: 0.0142

Gnomad4 OTH AF: 0.0428

Alfa AF: 0.0169 Hom.: 10

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
Cadd	Benign	1.0
Dann	Benign	0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs6457476; hg19: chr6-32009354;