6-32041574-C-T

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.*440C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00964 in 1,050,532 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.019 (28 hom., cov: 24)
  • Exomes 𝑓: 0.0081 (79 hom.)
• Consequence: CYP21A2 NM_000500.9 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.56

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=-0.9).
• BP6: Variant 6-32041574-C-T is Benign according to our data. Variant chr6-32041574-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1191218.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32041574-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0189 (2775/146984) while in subpopulation AMR AF= 0.0381 (571/14986). AF 95% confidence interval is 0.0355. There are 28 homozygotes in gnomad4. There are 1244 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP21A2	NM_000500.9	c.*440C>T		3_prime_UTR_variant	10/10	ENST00000644719.2
TNXB	NM_001365276.2	c.12634-124G>A		intron_variant		ENST00000644971.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2	c.*440C>T		3_prime_UTR_variant	10/10		NM_000500.9	P1
TNXB	ENST00000644971.2	c.12634-124G>A		intron_variant			NM_001365276.2

Frequencies

GnomAD3 genomes AF: 0.0189 AC: 2772 AN: 146860 Hom.: 28 Cov.: 24

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00112

Gnomad AMR AF: 0.0381

Gnomad ASJ AF: 0.0904

Gnomad EAS AF: 0.00117

Gnomad SAS AF: 0.00178

Gnomad FIN AF: 0.000955

Gnomad MID AF: 0.0226

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.0374

GnomAD4 exome AF: 0.00814 AC: 7357 AN: 903548 Hom.: 79 Cov.: 13 AF XY: 0.00786 AC XY: 3638 AN XY: 462990

Gnomad4 AFR exome AF: 0.0195

Gnomad4 AMR exome AF: 0.0218

Gnomad4 ASJ exome AF: 0.0571

Gnomad4 EAS exome AF: 0.000951

Gnomad4 SAS exome AF: 0.00115

Gnomad4 FIN exome AF: 0.00137

Gnomad4 NFE exome AF: 0.00645

Gnomad4 OTH exome AF: 0.0165

GnomAD4 genome AF: 0.0189 AC: 2775 AN: 146984 Hom.: 28 Cov.: 24 AF XY: 0.0173 AC XY: 1244 AN XY: 71752

Gnomad4 AFR AF: 0.0235

Gnomad4 AMR AF: 0.0381

Gnomad4 ASJ AF: 0.0904

Gnomad4 EAS AF: 0.00117

Gnomad4 SAS AF: 0.00178

Gnomad4 FIN AF: 0.000955

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.0370

Alfa AF: 0.0166 Hom.: 9

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	-0.90
Cadd	Benign	0.041
Dann	Benign	0.60

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: rs6457475; hg19: chr6-32009351; COSMIC: COSV64489863; COSMIC: COSV64489863;