rs150697472

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -1.57

Publications

6 publications found

Variant links:

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]

CYP21A2 links:

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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Illumina, PanelApp Australia, Orphanet
familial vesicoureteral reflux
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
vesicoureteral reflux 8
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

TNXB links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9 link	c.*12C>T		3_prime_UTR_variant	Exon 10 of 10	ENST00000644719.2	NP_000491.4	P08686Q16874Q08AG9
TNXB	NM_001365276.2 link	c.*203G>A		downstream_gene_variant		ENST00000644971.2	NP_001352205.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 link	c.*12C>T		3_prime_UTR_variant	Exon 10 of 10		NM_000500.9	ENSP00000496625.1		Q16874
TNXB	ENST00000644971.2 link	c.*203G>A		downstream_gene_variant			NM_001365276.2	ENSP00000496448.1		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.00911

AC:

1379

AN:

151452

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

Cov.:

AF XY:

0.0104

AC XY:

7465

AN XY:

715708

show subpopulations

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:

AN:

39604

South Asian (SAS)

AF:

0.0223

AC:

1910

AN:

85464

European-Finnish (FIN)

AF:

0.00102

AC:

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

651

1302

1952

2603

3254

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

384

768

1152

1536

1920

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00905

AC:

1371

AN:

151572

Hom.:

Cov.:

AF XY:

0.00922

AC XY:

683

AN XY:

74070

show subpopulations

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:

AN:

3336

East Asian (EAS)

AF:

0.00232

AC:

AN:

5176

South Asian (SAS)

AF:

0.0160

AC:

AN:

4798

European-Finnish (FIN)

AF:

0.000671

AC:

AN:

10438

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00877

AC:

594

AN:

67746

Other (OTH)

AF:

0.0229

AC:

AN:

2096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

117

175

234

292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0122

Hom.:

Bravo

AF:

0.00974

Asia WGS

AF:

0.0110

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Jul 06, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 18, 2024

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Available data are insufficient to determine the clinical significance of the variant at this time. Frequency data for this variant in the general population cannot be distinguished from that of the CYP21P pseudogene, and are therefore uninformative in assessment of variant pathogenicity. As reported in PMID: 28401898, the presence of this variant in individuals of European descent indicates a duplication of the CYP21A2 gene on the same chromosome as the allele containing the pathogenic variant c.955C>T. This extra gene copy functions normally, thus negating the effects of pathogenic variant(s) present in other copies, resulting in an effectively normal genotype. This has been demonstrated for people of European ancestry, it is not known at this time if the same association holds in other populations. In some published literature, this variant is referred to as 2842C>T, or 7842C>T. It has been previously reported as 1500C>T by Athena Diagnostics. In multiple individuals, this variant has been seen where an alternate explanation for disease was also identified, suggesting this variant is unlikely to cause disease. Computational tools yielded predictions that this variant is unlikely to have an effect on normal RNA splicing. -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Benign:1

Aug 15, 2024

Newborn Screening Ontario, Children's Hospital of Eastern Ontario (CHEO)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.7

(source)

DANN

Benign

0.70

PhyloP100

-1.6

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over