NM_000500.9:c.*390A>G

Variant names:

• chr6-32041524-A-G
• rs7774739
• NM_000500.9:c.*390A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000500.9(CYP21A2):​c.*390A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0175 in 1,150,876 control chromosomes in the GnomAD database, including 1,112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.049 (576 hom., cov: 24)
  • Exomes 𝑓: 0.013 (536 hom.)
• Consequence: CYP21A2 NM_000500.9 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0580
• Publications: 5 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 6-32041524-A-G is Benign according to our data. Variant chr6-32041524-A-G is described in ClinVar as Benign. ClinVar VariationId is 1183188.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 576 AR gene

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.*390A>G		3_prime_UTR	Exon 10 of 10	NP_000491.4
	TNXB	NM_001365276.2	MANE Select	c.12634-74T>C		intron	N/A	NP_001352205.1	P22105-3
	CYP21A2	NM_001128590.4		c.*390A>G		3_prime_UTR	Exon 9 of 9	NP_001122062.3	P08686-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP21A2	ENST00000644719.2	MANE Select	c.*390A>G		3_prime_UTR	Exon 10 of 10	ENSP00000496625.1	P08686-1
	TNXB	ENST00000644971.2	MANE Select	c.12634-74T>C		intron	N/A	ENSP00000496448.1	P22105-3
	TNXB	ENST00000451343.4	TSL:1	c.1921-74T>C		intron	N/A	ENSP00000407685.1	P22105-2

Frequencies

GnomAD3 genomes AF: 0.0493 AC: 7117 AN: 144322 Hom.: 569 Cov.: 24

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.0544

Gnomad ASJ AF: 0.0995

Gnomad EAS AF: 0.00704

Gnomad SAS AF: 0.00678

Gnomad FIN AF: 0.00144

Gnomad MID AF: 0.0325

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0657

GnomAD4 exome AF: 0.0129 AC: 12950 AN: 1006428 Hom.: 536 Cov.: 15 AF XY: 0.0123 AC XY: 6309 AN XY: 511274

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0974 AC: 1948 AN: 19994

American (AMR) AF: 0.0337 AC: 1137 AN: 33744

Ashkenazi Jewish (ASJ) AF: 0.0702 AC: 1498 AN: 21354

East Asian (EAS) AF: 0.00483 AC: 166 AN: 34370

South Asian (SAS) AF: 0.00515 AC: 365 AN: 70810

European-Finnish (FIN) AF: 0.00192 AC: 92 AN: 47834

Middle Eastern (MID) AF: 0.0257 AC: 116 AN: 4522

European-Non Finnish (NFE) AF: 0.00895 AC: 6530 AN: 729524

Other (OTH) AF: 0.0248 AC: 1098 AN: 44276

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0495 AC: 7149 AN: 144448 Hom.: 576 Cov.: 24 AF XY: 0.0463 AC XY: 3265 AN XY: 70472

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.125 AC: 4576 AN: 36666

American (AMR) AF: 0.0544 AC: 805 AN: 14808

Ashkenazi Jewish (ASJ) AF: 0.0995 AC: 334 AN: 3358

East Asian (EAS) AF: 0.00705 AC: 36 AN: 5106

South Asian (SAS) AF: 0.00699 AC: 31 AN: 4432

European-Finnish (FIN) AF: 0.00144 AC: 15 AN: 10398

Middle Eastern (MID) AF: 0.0414 AC: 12 AN: 290

European-Non Finnish (NFE) AF: 0.0168 AC: 1116 AN: 66514

Other (OTH) AF: 0.0664 AC: 133 AN: 2002

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0425 Hom.: 70

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	3.6
DANN	Benign	0.66
PhyloP100		-0.058
Mutation Taster		=100/0	polymorphism (auto)

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: rs7774739; hg19: chr6-32009301;