rs147821751

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6_Very_StrongBS2_Supporting

The NM_000500.9(CYP21A2):c.293-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,594,004 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 2 hom., cov: 31)

Exomes 𝑓: 0.0034 ( 31 hom. )

Consequence

CYP21A2
NM_000500.9 splice_region, intron

Scores

Splicing: ADA: 0.0002665

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -1.59

Publications

4 publications found

Variant links:

COSMIC-nc: COSV108220858

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008644223).

BP6

Variant 6-32039090-G-A is Benign according to our data. Variant chr6-32039090-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 256290.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	Effect	Exon rank	MANE	Protein
CYP21A2	NM_000500.9 link	c.293-4G>A	splice_region_variant, intron_variant	Intron 2 of 9	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001368143.2 link	c.-117G>A	5_prime_UTR_variant	Exon 3 of 10		NP_001355072.1
CYP21A2	NM_001368144.2 link	c.-117G>A	5_prime_UTR_variant	Exon 2 of 9		NP_001355073.1
CYP21A2	NM_001128590.4 link	c.203-4G>A	splice_region_variant, intron_variant	Intron 1 of 8		NP_001122062.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 link	c.293-4G>A		splice_region_variant, intron_variant	Intron 2 of 9		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes

AF:

0.00343

AC:

510

AN:

148674

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000644

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00335

Gnomad ASJ

AF:

0.00436

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00128

Gnomad FIN

AF:

0.00450

Gnomad MID

AF:

0.0258

Gnomad NFE

AF:

0.00516

Gnomad OTH

AF:

0.00680

GnomAD2 exomes

AF:

0.00329

AC:

761

AN:

231458

AF XY:

0.00363

show subpopulations

Gnomad AFR exome

AF:

0.000488

Gnomad AMR exome

AF:

0.00271

Gnomad ASJ exome

AF:

0.00304

Gnomad EAS exome

AF:

0.0000575

Gnomad FIN exome

AF:

0.00511

Gnomad NFE exome

AF:

0.00441

Gnomad OTH exome

AF:

0.00405

GnomAD4 exome

AF:

0.00336

AC:

4853

AN:

1445214

Hom.:

Cov.:

AF XY:

0.00344

AC XY:

2466

AN XY:

717448

show subpopulations

African (AFR)

AF:

0.000484

AC:

AN:

33070

American (AMR)

AF:

0.00327

AC:

142

AN:

43452

Ashkenazi Jewish (ASJ)

AF:

0.00393

AC:

101

AN:

25714

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39044

South Asian (SAS)

AF:

0.00177

AC:

149

AN:

84128

European-Finnish (FIN)

AF:

0.00481

AC:

247

AN:

51402

Middle Eastern (MID)

AF:

0.0107

AC:

AN:

5632

European-Non Finnish (NFE)

AF:

0.00355

AC:

3912

AN:

1103128

Other (OTH)

AF:

0.00377

AC:

225

AN:

59644

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

221

442

662

883

1104

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

256

384

512

640

<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:

0.00341

AC:

508

AN:

148790

Hom.:

Cov.:

AF XY:

0.00333

AC XY:

241

AN XY:

72384

show subpopulations

African (AFR)

AF:

0.000642

AC:

AN:

40524

American (AMR)

AF:

0.00335

AC:

AN:

14928

Ashkenazi Jewish (ASJ)

AF:

0.00436

AC:

AN:

3444

East Asian (EAS)

AF:

0.00

AC:

AN:

4906

South Asian (SAS)

AF:

0.00128

AC:

AN:

4690

European-Finnish (FIN)

AF:

0.00450

AC:

AN:

9788

Middle Eastern (MID)

AF:

0.0207

AC:

AN:

290

European-Non Finnish (NFE)

AF:

0.00516

AC:

347

AN:

67230

Other (OTH)

AF:

0.00672

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.529

Heterozygous variant carriers

102

127

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:

0.00468

Hom.:

Bravo

AF:

0.00314

ESP6500AA

AF:

0.000909

AC:

ESP6500EA

AF:

0.00523

AC:

ExAC

AF:

0.00318

AC:

386

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Oct 25, 2024

Athena Diagnostics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

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 -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 28, 2023

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Likely 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:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.53

(source)

DANN

Benign

0.81

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.0083

LIST_S2

Benign

0.27

MetaRNN

Benign

0.0086

MetaSVM

Benign

-1.0

PhyloP100

-1.6

PROVEAN

Benign

0.31

REVEL

Benign

0.020

Sift

Benign

0.31

Sift4G

Uncertain

0.024

MVP

0.46

ClinPred

0.0024

GERP RS

-6.2

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00027

dbscSNV1_RF

Benign

0.020

SpliceAI score (max)

0.050

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