rs6455

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000500.9(CYP21A2):c.318G>A(p.Pro106Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0016 in 1,484,242 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P106P) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0085 ( 21 hom., cov: 31)

Exomes 𝑓: 0.00086 ( 11 hom. )

Consequence

CYP21A2
NM_000500.9 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -2.25

Publications

13 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 6-32039119-G-A is Benign according to our data. Variant chr6-32039119-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-2.26 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00852 (1220/143214) while in subpopulation AFR AF = 0.029 (1137/39224). AF 95% confidence interval is 0.0276. There are 21 homozygotes in GnomAd4. There are 595 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
CYP21A2	NM_000500.9 link	c.318G>A	p.Pro106Pro	synonymous_variant	Exon 3 of 10	ENST00000644719.2	NP_000491.4
CYP21A2	NM_001128590.4 link	c.228G>A	p.Pro76Pro	synonymous_variant	Exon 2 of 9		NP_001122062.3
CYP21A2	NM_001368143.2 link	c.-88G>A		5_prime_UTR_variant	Exon 3 of 10		NP_001355072.1
CYP21A2	NM_001368144.2 link	c.-88G>A		5_prime_UTR_variant	Exon 2 of 9		NP_001355073.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 link	c.318G>A	p.Pro106Pro	synonymous_variant	Exon 3 of 10		NM_000500.9	ENSP00000496625.1

Frequencies

GnomAD3 genomes

AF:

0.00851

AC:

1218

AN:

143104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00453

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000239

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000763

Gnomad OTH

AF:

0.00655

GnomAD2 exomes

AF:

0.00190

AC:

464

AN:

244218

AF XY:

0.00139

show subpopulations

Gnomad AFR exome

AF:

0.0245

Gnomad AMR exome

AF:

0.00170

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000155

Gnomad OTH exome

AF:

0.000674

GnomAD4 exome

AF:

0.000858

AC:

1150

AN:

1341028

Hom.:

Cov.:

AF XY:

0.000767

AC XY:

510

AN XY:

665182

show subpopulations

African (AFR)

AF:

0.0261

AC:

786

AN:

30166

American (AMR)

AF:

0.00173

AC:

AN:

41596

Ashkenazi Jewish (ASJ)

AF:

0.0000460

AC:

AN:

21740

East Asian (EAS)

AF:

0.0000336

AC:

AN:

29728

South Asian (SAS)

AF:

0.000166

AC:

AN:

84294

European-Finnish (FIN)

AF:

0.00

AC:

AN:

43572

Middle Eastern (MID)

AF:

0.00193

AC:

AN:

5188

European-Non Finnish (NFE)

AF:

0.000151

AC:

156

AN:

1032490

Other (OTH)

AF:

0.00211

AC:

110

AN:

52254

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00852

AC:

1220

AN:

143214

Hom.:

Cov.:

AF XY:

0.00858

AC XY:

595

AN XY:

69336

show subpopulations

African (AFR)

AF:

0.0290

AC:

1137

AN:

39224

American (AMR)

AF:

0.00453

AC:

AN:

14358

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3386

East Asian (EAS)

AF:

0.00

AC:

AN:

4346

South Asian (SAS)

AF:

0.00

AC:

AN:

4190

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8964

Middle Eastern (MID)

AF:

0.00

AC:

AN:

274

European-Non Finnish (NFE)

AF:

0.0000763

AC:

AN:

65572

Other (OTH)

AF:

0.00649

AC:

AN:

2002

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.000548

Hom.:

Bravo

AF:

0.00916

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 15, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

4.1

(source)

DANN

Benign

0.64

PhyloP100

-2.3

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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