rs6473

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 1P and 12B. PP2BP4_StrongBP6_Very_Strong

The NM_000500.9(CYP21A2):c.1481G>A(p.Ser494Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S494S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0057 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0030 ( 261 hom. )

Failed GnomAD Quality Control

Consequence

CYP21A2
NM_000500.9 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.227

Publications

9 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 -11 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.006213218).

BP6

Variant 6-32041127-G-A is Benign according to our data. Variant chr6-32041127-G-A is described in ClinVar as [Benign]. Clinvar id is 193596.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.1481G>A	p.Ser494Asn	missense_variant	Exon 10 of 10	ENST00000644719.2	NP_000491.4	P08686Q16874Q08AG9
TNXB	NM_001365276.2 link	c.*222C>T		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.1481G>A	p.Ser494Asn	missense_variant	Exon 10 of 10		NM_000500.9	ENSP00000496625.1		Q16874
TNXB	ENST00000644971.2 link	c.*222C>T		downstream_gene_variant			NM_001365276.2	ENSP00000496448.1		P22105-3

Frequencies

GnomAD3 genomes

AF:

0.00566

AC:

782

AN:

138106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00188

Gnomad AMI

AF:

0.0291

Gnomad AMR

AF:

0.00497

Gnomad ASJ

AF:

0.00716

Gnomad EAS

AF:

0.00167

Gnomad SAS

AF:

0.0187

Gnomad FIN

AF:

0.00771

Gnomad MID

AF:

0.0109

Gnomad NFE

AF:

0.00697

Gnomad OTH

AF:

0.00738

GnomAD2 exomes

AF:

0.000375

AC:

AN:

237558

AF XY:

0.000339

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000589

Gnomad ASJ exome

AF:

0.000737

Gnomad EAS exome

AF:

0.000169

Gnomad FIN exome

AF:

0.000112

Gnomad NFE exome

AF:

0.000529

Gnomad OTH exome

AF:

0.000516

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00301

AC:

4166

AN:

1383480

Hom.:

261

Cov.:

AF XY:

0.00309

AC XY:

2125

AN XY:

687484

show subpopulations

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

African (AFR)

AF:

0.00142

AC:

AN:

32398

American (AMR)

AF:

0.00271

AC:

116

AN:

42798

Ashkenazi Jewish (ASJ)

AF:

0.0106

AC:

252

AN:

23780

East Asian (EAS)

AF:

0.000721

AC:

AN:

38850

South Asian (SAS)

AF:

0.00565

AC:

449

AN:

79458

European-Finnish (FIN)

AF:

0.00553

AC:

245

AN:

44340

Middle Eastern (MID)

AF:

0.00398

AC:

AN:

4266

European-Non Finnish (NFE)

AF:

0.00262

AC:

2780

AN:

1061160

Other (OTH)

AF:

0.00413

AC:

233

AN:

56430

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.257

Heterozygous variant carriers

488

976

1464

1952

2440

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00566

AC:

782

AN:

138240

Hom.:

Cov.:

AF XY:

0.00579

AC XY:

392

AN XY:

67722

show subpopulations

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

African (AFR)

AF:

0.00190

AC:

AN:

39450

American (AMR)

AF:

0.00496

AC:

AN:

14108

Ashkenazi Jewish (ASJ)

AF:

0.00716

AC:

AN:

2934

East Asian (EAS)

AF:

0.00167

AC:

AN:

4780

South Asian (SAS)

AF:

0.0182

AC:

AN:

4058

European-Finnish (FIN)

AF:

0.00771

AC:

AN:

9464

Middle Eastern (MID)

AF:

0.0117

AC:

AN:

256

European-Non Finnish (NFE)

AF:

0.00697

AC:

422

AN:

60546

Other (OTH)

AF:

0.00780

AC:

AN:

1922

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.263

Heterozygous variant carriers

192

289

385

481

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00676

Hom.:

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Jul 06, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Benign:1

Jun 01, 2022

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

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.46

(source)

DANN

Benign

0.60

Eigen

Benign

-0.99

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.021

M_CAP

Benign

0.068

MetaRNN

Benign

0.0062

T;T;T;T

MetaSVM

Benign

-1.0

PhyloP100

-0.23

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.50

N;.;N;.

REVEL

Benign

0.076

Sift

Benign

0.45

T;.;T;.

Sift4G

Benign

1.0

T;.;T;.

Polyphen

0.0030

B;B;.;B

Vest4

0.041

MVP

0.25

MPC

0.0098

ClinPred

0.0087

GERP RS

2.6

gMVP

0.46

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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rs6473

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