rs150697472

chr6-32041146-C-T

Variant summary

Our verdict is Benign. Variant got -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:1

Conservation

PhyloP100: -1.57

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 585746.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}. Variant chr6-32041146-C-T is described in Lovd as [Benign].

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/exons	MANE	UniProt
CYP21A2	NM_000500.9 linkuse as main transcript	c.*12C>T		3_prime_UTR_variant	10/10	ENST00000644719.2
TNXB	NM_001365276.2 linkuse as main transcript			downstream_gene_variant		ENST00000644971.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP21A2	ENST00000644719.2 linkuse as main transcript	c.*12C>T		3_prime_UTR_variant	10/10		NM_000500.9	P1
TNXB	ENST00000644971.2 linkuse as main transcript			downstream_gene_variant			NM_001365276.2		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

GnomAD3 exomes

AF:

0.0110

AC:

2602

AN:

237494

Hom.:

AF XY:

0.0121

AC XY:

1567

AN XY:

130024

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 SAS exome

AF:

0.0231

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

Gnomad4 AFR exome

AF:

0.00768

Gnomad4 AMR exome

AF:

0.00987

Gnomad4 ASJ exome

AF:

0.0216

Gnomad4 EAS exome

AF:

0.000959

Gnomad4 SAS exome

AF:

0.0223

Gnomad4 FIN exome

AF:

0.00102

Gnomad4 NFE exome

AF:

0.00902

Gnomad4 OTH exome

AF:

0.0130

GnomAD4 genome

AF:

0.00905

AC:

1371

AN:

151572

Hom.:

Cov.:

AF XY:

0.00922

AC XY:

683

AN XY:

74070

show subpopulations

Gnomad4 AFR

AF:

0.00837

Gnomad4 AMR

AF:

0.0124

Gnomad4 ASJ

AF:

0.0219

Gnomad4 EAS

AF:

0.00232

Gnomad4 SAS

AF:

0.0160

Gnomad4 FIN

AF:

0.000671

Gnomad4 NFE

AF:

0.00877

Gnomad4 OTH

AF:

0.0229

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:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 18, 2023	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 (http://gnomad.broadinstitute.org). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

Cadd

Benign

1.7

Dann

Benign

0.70

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over