rs150697472

Variant names:

• chr6-32041146-C-T
• rs150697472
• NM_000500.9:c.*12C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_000500.9(CYP21A2):​c.*12C>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 0.0098 in 1,589,556 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0090 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0099 (22 hom.)
• Consequence: CYP21A2 NM_000500.9 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -1.57
• Publications: 6 publications found

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]

TNXB Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome due to tenascin-X deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Illumina, Genomics England PanelApp, PanelApp Australia
• familial vesicoureteral reflux

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• vesicoureteral reflux 8

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-32041146-C-T is Benign according to our data. Variant chr6-32041146-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 585746.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0591 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000500.9. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	NM_000500.9	MANE Select	c.*12C>T		3_prime_UTR	Exon 10 of 10	NP_000491.4
	CYP21A2	NM_001128590.4		c.*12C>T		3_prime_UTR	Exon 9 of 9	NP_001122062.3	P08686-2
	CYP21A2	NM_001368143.2		c.*12C>T		3_prime_UTR	Exon 10 of 10	NP_001355072.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.*12C>T		3_prime_UTR	Exon 10 of 10	ENSP00000496625.1	P08686-1
	CYP21A2	ENST00000960600.1		c.*12C>T		3_prime_UTR	Exon 10 of 10	ENSP00000630659.1
	CYP21A2	ENST00000960597.1		c.*12C>T		3_prime_UTR	Exon 10 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes AF: 0.00911 AC: 1379 AN: 151452 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00840

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.0219

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0162

Gnomad FIN AF: 0.000671

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.00877

Gnomad OTH AF: 0.0236

GnomAD2 exomes AF: 0.0110 AC: 2602 AN: 237494 AF XY: 0.0121

Gnomad AFR exome AF: 0.00971

Gnomad AMR exome AF: 0.00927

Gnomad ASJ exome AF: 0.0208

Gnomad EAS exome AF: 0.00118

Gnomad FIN exome AF: 0.000638

Gnomad NFE exome AF: 0.0103

Gnomad OTH exome AF: 0.0174

GnomAD4 exome AF: 0.00988 AC: 14206 AN: 1437984 Hom.: 22 Cov.: 33 AF XY: 0.0104 AC XY: 7465 AN XY: 715708

African (AFR) AF: 0.00768 AC: 256 AN: 33348

American (AMR) AF: 0.00987 AC: 439 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 550 AN: 25424

East Asian (EAS) AF: 0.000959 AC: 38 AN: 39604

South Asian (SAS) AF: 0.0223 AC: 1910 AN: 85464

European-Finnish (FIN) AF: 0.00102 AC: 48 AN: 47264

Middle Eastern (MID) AF: 0.0654 AC: 281 AN: 4296

European-Non Finnish (NFE) AF: 0.00902 AC: 9908 AN: 1098484

Other (OTH) AF: 0.0130 AC: 776 AN: 59638

GnomAD4 genome AF: 0.00905 AC: 1371 AN: 151572 Hom.: 0 Cov.: 33 AF XY: 0.00922 AC XY: 683 AN XY: 74070

African (AFR) AF: 0.00837 AC: 348 AN: 41566

American (AMR) AF: 0.0124 AC: 189 AN: 15224

Ashkenazi Jewish (ASJ) AF: 0.0219 AC: 73 AN: 3336

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5176

South Asian (SAS) AF: 0.0160 AC: 77 AN: 4798

European-Finnish (FIN) AF: 0.000671 AC: 7 AN: 10438

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.00877 AC: 594 AN: 67746

Other (OTH) AF: 0.0229 AC: 48 AN: 2096

Alfa AF: 0.0122 Hom.: 1

Bravo AF: 0.00974

Asia WGS AF: 0.0110 AC: 37 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	ADRENAL HYPERPLASIA, CONGENITAL, DUE TO 21-HYDROXYLASE DEFICIENCY (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.7
DANN	Benign	0.70
PhyloP100		-1.6
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs150697472; hg19: chr6-32008923; COSMIC: COSV64483672; COSMIC: COSV64483672;