6-32039548-C-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_000500.9(CYP21A2):c.552C>G(p.Asp184Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,580,942 control chromosomes in the GnomAD database, including 50 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0020 ( 48 hom. )

Consequence

CYP21A2
NM_000500.9 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5O:1

Conservation

PhyloP100: -0.725

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 Gene-Disease associations (from GenCC):

classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, salt wasting form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency, simple virilizing form
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CYP21A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 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=0.0114969015).

BP6

Variant 6-32039548-C-G is Benign according to our data. Variant chr6-32039548-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 65609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9 link	c.552C>G	p.Asp184Glu	missense_variant, splice_region_variant	Exon 5 of 10	ENST00000644719.2	NP_000491.4	P08686Q16874Q08AG9
CYP21A2	NM_001128590.4 link	c.462C>G	p.Asp154Glu	missense_variant, splice_region_variant	Exon 4 of 9		NP_001122062.3	P08686Q08AG9
CYP21A2	NM_001368143.2 link	c.147C>G	p.Asp49Glu	missense_variant, splice_region_variant	Exon 5 of 10		NP_001355072.1
CYP21A2	NM_001368144.2 link	c.147C>G	p.Asp49Glu	missense_variant, splice_region_variant	Exon 4 of 9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 link	c.552C>G	p.Asp184Glu	missense_variant, splice_region_variant	Exon 5 of 10		NM_000500.9	ENSP00000496625.1		Q16874

Frequencies

GnomAD3 genomes

AF:

0.00300

AC:

453

AN:

150816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00107

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00691

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.000977

Gnomad SAS

AF:

0.00230

Gnomad FIN

AF:

0.00800

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00292

Gnomad OTH

AF:

0.00341

GnomAD2 exomes

AF:

0.00145

AC:

308

AN:

211870

AF XY:

0.00136

show subpopulations

Gnomad AFR exome

AF:

0.000764

Gnomad AMR exome

AF:

0.00392

Gnomad ASJ exome

AF:

0.000214

Gnomad EAS exome

AF:

0.000379

Gnomad FIN exome

AF:

0.00110

Gnomad NFE exome

AF:

0.00133

Gnomad OTH exome

AF:

0.00164

GnomAD4 exome

AF:

0.00197

AC:

2812

AN:

1430014

Hom.:

Cov.:

AF XY:

0.00200

AC XY:

1419

AN XY:

708910

show subpopulations

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

African (AFR)

AF:

0.000852

AC:

AN:

32878

American (AMR)

AF:

0.00487

AC:

192

AN:

39452

Ashkenazi Jewish (ASJ)

AF:

0.000350

AC:

AN:

25710

East Asian (EAS)

AF:

0.000755

AC:

AN:

38394

South Asian (SAS)

AF:

0.00160

AC:

133

AN:

83138

European-Finnish (FIN)

AF:

0.00658

AC:

336

AN:

51100

Middle Eastern (MID)

AF:

0.000524

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00178

AC:

1946

AN:

1094542

Other (OTH)

AF:

0.00230

AC:

136

AN:

59078

⚠️ 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: 0.360

Heterozygous variant carriers

125

249

374

498

623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

162

216

270

<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:

0.00301

AC:

455

AN:

150928

Hom.:

Cov.:

AF XY:

0.00294

AC XY:

217

AN XY:

73740

show subpopulations

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

African (AFR)

AF:

0.00109

AC:

AN:

41318

American (AMR)

AF:

0.00697

AC:

103

AN:

14772

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

3472

East Asian (EAS)

AF:

0.000979

AC:

AN:

5106

South Asian (SAS)

AF:

0.00230

AC:

AN:

4784

European-Finnish (FIN)

AF:

0.00800

AC:

AN:

10378

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00292

AC:

198

AN:

67818

Other (OTH)

AF:

0.00337

AC:

AN:

2076

⚠️ 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: 0.344

Heterozygous variant carriers

106

132

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:

0.00123

Hom.:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000588

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Benign:2Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Mar 16, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

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

- -

not provided

Benign:2

Apr 05, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CYP21A2: BP4, BS2 -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

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

-0.64

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.5

(source)

DANN

Benign

0.76

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0022

M_CAP

Benign

0.041

MetaRNN

Benign

0.011

T;T;T;T

MetaSVM

Benign

-1.1

PhyloP100

-0.72

PrimateAI

Benign

0.30

PROVEAN

Benign

0.21

N;.;N;.

REVEL

Benign

0.034

Sift

Benign

1.0

T;.;T;.

Sift4G

Benign

1.0

T;.;T;.

Polyphen

0.0010

B;B;.;B

Vest4

0.069

MutPred

0.44

Loss of ubiquitination at K183 (P = 0.0962);Loss of ubiquitination at K183 (P = 0.0962);.;Loss of ubiquitination at K183 (P = 0.0962);

MVP

0.39

MPC

0.43

ClinPred

0.000024

GERP RS

-3.4

gMVP

0.076

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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