CYP21A2 p.Val282Leu

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is . The variant received 8 classification points (ACMG Germline Pathogenicity v2019): 8P and 0B. PS3PP5_Strong

The NM_000500.9(CYP21A2):c.844G>T (p.Val282Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant has a gnomAD grpmax filtering allele frequency (95% CI) of 0.0255, indicating it is observed in the general population. Note: a gnomAD entry for this variant shows a statistical allele-bias signature, consistent with mosaic/somatic contamination (e.g. age-related clonal hematopoiesis) rather than true inherited population frequency — this frequency should not be read as evidence of a common, benign germline variant. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000245595: "In vitro functional studies indicate that the p.Val282Leu variant may impact protein function (Tusie-Luna 1990, Barbaro 2015)."" and additional evidence is available in ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.V282L: not_provided (ClinVar VariationId 65610) This exact variant is curated in the UniProt human variants database as Pathogenic, associated with Adrenal hyperplasia 3 (AH3).

Frequency

Genomes: 𝑓 0.011 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0044 ( 16 hom. )

Consequence

CYP21A2
NM_000500.9 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:40O:1

Conservation

PhyloP100: 2.60

Publications

287 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: Laboratory for Molecular Medicine, Myriad Women's Health, Labcorp Genetics (formerly Invitae)
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:

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new If you want to explore the variant's impact on the transcript NM_000500.9, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 points.

PS3

Well-established functional study supports damaging effect (PS3); SCV000245595: "In vitro functional studies indicate that the p.Val282Leu variant may impact protein function (Tusie-Luna 1990, Barbaro 2015)."; SCV000494239: Functional studies found that co-expression of this mutant protein and wild-type (WT) protein results in a dominant negative effect on the enzymatic activity of WT protein (Felix-Lopez et al. 2003). Other studies indicate reduced enzyme activity with the p.Val281Leu allele (Wu and Chung 1991, Haider et al. 2013).; SCV001142354: "In vitro functional studies indicate that the p.Val282Leu variant may impact protein function." PMID:24953648; SCV002521256: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 20661889, 21609351).; SCV003852661: Experimental studies have shown that this missense change affects CYP21A2 function (Karlsson L et al., 2019).; SCV005200514: "backed by functional studies (PS3)."; SCV005416532: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV000263011: Functional analysis demonstrated that the p.V282L alteration reduces 21-hydroxylase activity by about 50% due to an increase in chain length resulting in relatively modest steric clashes in the I-helix of the protein (Haider, 2013; New, 2013).; SCV000841748: Expression of this variant results in reduced enzymatic activity compared to wild type (PMID: 2249999, 24953648).; SCV001552008: Functional studies have found that the p.Val282Leu variant results in a 20-50% reduction in enzymatic activity (Tusie-Luna_1990_PMID:2249999).; SCV002242900: Experimental studies have shown that this missense change affects CYP21A2 function (PMID: 1864962, 2249999, 31344365).; SCV002051107: The most pronounced variant effect results in 30%-50% of normal activity (White_2000).

PP5

ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000500.9. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP21A2	NM_000500.9	MANE Select	c.844G>T	p.Val282Leu	missense	Exon 7 of 10	NP_000491.4
CYP21A2	NM_001128590.4		c.754G>T	p.Val252Leu	missense	Exon 6 of 9	NP_001122062.3	P08686-2
CYP21A2	NM_001368143.2		c.439G>T	p.Val147Leu	missense	Exon 7 of 10	NP_001355072.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CYP21A2	ENST00000644719.2	MANE Select	c.844G>T	p.Val282Leu	missense	Exon 7 of 10	ENSP00000496625.1	P08686-1
CYP21A2	ENST00000960600.1		c.880G>T	p.Val294Leu	missense	Exon 7 of 10	ENSP00000630659.1
CYP21A2	ENST00000960597.1		c.853G>T	p.Val285Leu	missense	Exon 7 of 10	ENSP00000630656.1

Frequencies

GnomAD3 genomes

AF:

0.0109

AC:

1638

AN:

150884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0276

Gnomad ASJ

AF:

0.0723

Gnomad EAS

AF:

0.00213

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00113

Gnomad MID

AF:

0.0160

Gnomad NFE

AF:

0.0104

Gnomad OTH

AF:

0.0245

GnomAD2 exomes

AF:

0.00528

AC:

1280

AN:

242232

AF XY:

0.00442

show subpopulations

Gnomad AFR exome

AF:

0.00295

Gnomad AMR exome

AF:

0.0134

Gnomad ASJ exome

AF:

0.0233

Gnomad EAS exome

AF:

0.000932

Gnomad FIN exome

AF:

0.000880

Gnomad NFE exome

AF:

0.00447

Gnomad OTH exome

AF:

0.00865

GnomAD4 exome

AF:

0.00439

AC:

6337

AN:

1444170

Hom.:

Cov.:

AF XY:

0.00429

AC XY:

3082

AN XY:

718662

show subpopulations

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

African (AFR)

AF:

0.00297

AC:

AN:

33278

American (AMR)

AF:

0.0149

AC:

661

AN:

44246

Ashkenazi Jewish (ASJ)

AF:

0.0452

AC:

1126

AN:

24906

East Asian (EAS)

AF:

0.000631

AC:

AN:

39634

South Asian (SAS)

AF:

0.000905

AC:

AN:

86152

European-Finnish (FIN)

AF:

0.00136

AC:

AN:

52258

Middle Eastern (MID)

AF:

0.00959

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.00334

AC:

3669

AN:

1098614

Other (OTH)

AF:

0.00932

AC:

554

AN:

59454

⚠️ 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: 0.279

Heterozygous variant carriers

586

1172

1758

2344

2930

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

144

180

<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:

0.0109

AC:

1639

AN:

150998

Hom.:

Cov.:

AF XY:

0.00968

AC XY:

715

AN XY:

73886

show subpopulations

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

African (AFR)

AF:

0.00486

AC:

201

AN:

41396

American (AMR)

AF:

0.0276

AC:

415

AN:

15012

Ashkenazi Jewish (ASJ)

AF:

0.0723

AC:

238

AN:

3290

East Asian (EAS)

AF:

0.00214

AC:

AN:

5150

South Asian (SAS)

AF:

0.00125

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00113

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0174

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0104

AC:

701

AN:

67460

Other (OTH)

AF:

0.0242

AC:

AN:

2062

⚠️ 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: 0.312

Heterozygous variant carriers

107

215

322

430

537

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:

0.00714

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

21-Hydroxylase-Deficient Congenital Adrenal Hyperplasia (24)

not provided (12)

Adenoma, cortisol-producing (1)

Carcinoma, adrenocortical, androgen-secreting (1)

Congenital adrenal hyperplasia (1)

CYP21A2-related disorder (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.064

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Uncertain

0.99

Eigen

Benign

0.054

Eigen_PC

Benign

0.10

FATHMM_MKL

Uncertain

0.88

MetaRNN

Benign

0.0097

MetaSVM

Benign

-0.97

PhyloP100

2.6

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.90

REVEL

Uncertain

0.31

Sift

Benign

0.61

Sift4G

Benign

0.41

gMVP

0.60

Mutation Taster

=11/89

disease causing (ClinVar)

(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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over