6-32041097-G-C

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM5PP2PP5_Very_Strong

The NM_000500.9(CYP21A2):c.1451G>C(p.Arg484Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000682 in 1,582,546 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R484W) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00072 ( 0 hom. )

Consequence

CYP21A2
NM_000500.9 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 1.19

Publications

19 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: Pathogenic. The variant received 11 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr6-32041096-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 1455875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 52 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Trascript score misZ: 1.8021 (below the threshold of 3.09). GenCC associations: The gene is linked to classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form.

PP5

Variant 6-32041097-G-C is Pathogenic according to our data. Variant chr6-32041097-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1264335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9 link	c.1451G>C	p.Arg484Pro	missense_variant	Exon 10 of 10	ENST00000644719.2	NP_000491.4
TNXB	NM_001365276.2 link	c.*252C>G		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.1451G>C	p.Arg484Pro	missense_variant	Exon 10 of 10		NM_000500.9	ENSP00000496625.1
TNXB	ENST00000644971.2 link	c.*252C>G		downstream_gene_variant			NM_001365276.2	ENSP00000496448.1

Frequencies

GnomAD3 genomes

AF:

0.000352

AC:

AN:

150672

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000726

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000132

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000712

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000330

AC:

AN:

227246

AF XY:

0.000305

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000299

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000678

Gnomad OTH exome

AF:

0.000177

GnomAD4 exome

AF:

0.000717

AC:

1027

AN:

1431756

Hom.:

Cov.:

AF XY:

0.000679

AC XY:

484

AN XY:

712384

show subpopulations

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

African (AFR)

AF:

0.000180

AC:

AN:

33258

American (AMR)

AF:

0.0000685

AC:

AN:

43792

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25422

East Asian (EAS)

AF:

0.00

AC:

AN:

39324

South Asian (SAS)

AF:

0.0000470

AC:

AN:

85062

European-Finnish (FIN)

AF:

0.0000457

AC:

AN:

43740

Middle Eastern (MID)

AF:

0.000682

AC:

AN:

4402

European-Non Finnish (NFE)

AF:

0.000901

AC:

989

AN:

1097380

Other (OTH)

AF:

0.000337

AC:

AN:

59376

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.312

Heterozygous variant carriers

140

209

279

349

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

114

152

190

<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:

0.000351

AC:

AN:

150790

Hom.:

Cov.:

AF XY:

0.000231

AC XY:

AN XY:

73644

show subpopulations

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

African (AFR)

AF:

0.0000724

AC:

AN:

41430

American (AMR)

AF:

0.000132

AC:

AN:

15168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3346

East Asian (EAS)

AF:

0.00

AC:

AN:

5058

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10302

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000712

AC:

AN:

67412

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.314

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000373

Hom.:

ExAC

AF:

0.000283

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Pathogenic:5Uncertain:1

May 22, 2022

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.033%). However, 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. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.66; 3Cnet: 0.29). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV001264335). A different missense change at the same codon (p.Arg484Gln, p.Arg484Trp) has been reported to be associated with CYP21A2 related disorder (ClinVar ID: VCV000585750 / PMID: 12915679, 14715874). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline.

May 06, 2022

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Absent from controls (or at extremely low frequency if recessive) in Genome Aggregation Database, Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium.;Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.;For recessive disorders, detected in trans with a pathogenic variant.;Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.;Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease.

Molecular Endocrinology Laboratory, Christian Medical College

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Apr 04, 2023

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Mar 10, 2021

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

not provided

Pathogenic:2

Jun 25, 2024

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The CYP21A2 c.1451G>C (p.Arg484Pro) pathogenic variant (also known as R483P) has been described to cause markedly decreased CYP21A2 activity and stability, and identified in individuals with CAH, mainly of the salt-wasting phenotype (PMID: 9497336 (1998), 15994751 (2005), 20926536 (2011), and 23359698 (2013), 32616876 (2020)). Based on the available information, this variant is classified as pathogenic.

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.70

BayesDel_addAF

Benign

-0.030

BayesDel_noAF

Uncertain

0.080

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;.;.;.

Eigen

Benign

-0.037

Eigen_PC

Benign

-0.057

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.0

.;.;.;.

M_CAP

Pathogenic

0.95

MetaRNN

Uncertain

0.56

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Benign

0.0

.;.;.;.

PhyloP100

1.2

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-4.4

D;.;D;.

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

D;.;D;.

Sift4G

Pathogenic

0.0

D;.;D;.

Vest4

0.73

ClinPred

0.28

GERP RS

4.2

gMVP

0.97

Mutation Taster

=4/96

disease causing

(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