6-32038540-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000500.9(CYP21A2):c.118C>T(p.Leu40Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.833 in 150,170 control chromosomes in the GnomAD database, including 51,682 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.83 ( 51682 hom., cov: 30)

Exomes 𝑓: 0.79 ( 439449 hom. )

Failed GnomAD Quality Control

Consequence

CYP21A2
NM_000500.9 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.0860

Publications

12 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=-0.58).

BP6

Variant 6-32038540-C-T is Benign according to our data. Variant chr6-32038540-C-T is described in ClinVar as Benign. ClinVar VariationId is 256286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.086 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.901 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP21A2	NM_000500.9 link	c.118C>T	p.Leu40Leu	synonymous_variant	Exon 1 of 10	ENST00000644719.2	NP_000491.4	P08686Q16874Q08AG9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP21A2	ENST00000644719.2 link	c.118C>T	p.Leu40Leu	synonymous_variant	Exon 1 of 10		NM_000500.9	ENSP00000496625.1		Q16874

Frequencies

GnomAD3 genomes

AF:

0.833

AC:

124960

AN:

150056

Hom.:

51626

Cov.:

show subpopulations

Gnomad AFR

AF:

0.908

Gnomad AMI

AF:

0.916

Gnomad AMR

AF:

0.846

Gnomad ASJ

AF:

0.893

Gnomad EAS

AF:

0.751

Gnomad SAS

AF:

0.823

Gnomad FIN

AF:

0.816

Gnomad MID

AF:

0.890

Gnomad NFE

AF:

0.789

Gnomad OTH

AF:

0.846

GnomAD2 exomes

AF:

0.794

AC:

182802

AN:

230114

AF XY:

0.793

show subpopulations

Gnomad AFR exome

AF:

0.885

Gnomad AMR exome

AF:

0.842

Gnomad ASJ exome

AF:

0.874

Gnomad EAS exome

AF:

0.710

Gnomad FIN exome

AF:

0.791

Gnomad NFE exome

AF:

0.769

Gnomad OTH exome

AF:

0.790

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.787

AC:

1141026

AN:

1450538

Hom.:

439449

Cov.:

121

AF XY:

0.787

AC XY:

567343

AN XY:

720666

show subpopulations

African (AFR)

AF:

0.904

AC:

30009

AN:

33198

American (AMR)

AF:

0.846

AC:

36718

AN:

43406

Ashkenazi Jewish (ASJ)

AF:

0.881

AC:

22813

AN:

25900

East Asian (EAS)

AF:

0.723

AC:

28431

AN:

39318

South Asian (SAS)

AF:

0.813

AC:

69105

AN:

84980

European-Finnish (FIN)

AF:

0.790

AC:

41249

AN:

52244

Middle Eastern (MID)

AF:

0.803

AC:

4581

AN:

5704

European-Non Finnish (NFE)

AF:

0.778

AC:

860689

AN:

1105900

Other (OTH)

AF:

0.792

AC:

47431

AN:

59888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.520

Heterozygous variant carriers

14223

28445

42668

56890

71113

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20856

41712

62568

83424

104280

<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:

0.833

AC:

125073

AN:

150170

Hom.:

51682

Cov.:

AF XY:

0.832

AC XY:

61039

AN XY:

73322

show subpopulations

African (AFR)

AF:

0.909

AC:

37015

AN:

40738

American (AMR)

AF:

0.846

AC:

12778

AN:

15096

Ashkenazi Jewish (ASJ)

AF:

0.893

AC:

3081

AN:

3452

East Asian (EAS)

AF:

0.752

AC:

3742

AN:

4978

South Asian (SAS)

AF:

0.822

AC:

3926

AN:

4774

European-Finnish (FIN)

AF:

0.816

AC:

8519

AN:

10438

Middle Eastern (MID)

AF:

0.886

AC:

257

AN:

290

European-Non Finnish (NFE)

AF:

0.789

AC:

53162

AN:

67418

Other (OTH)

AF:

0.848

AC:

1765

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.564

Heterozygous variant carriers

845

1689

2534

3378

4223

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

876

1752

2628

3504

4380

<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:

0.774

Hom.:

4117

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

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

Jul 30, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.58

CADD

Benign

6.3

(source)

DANN

Benign

0.84

PhyloP100

0.086

PromoterAI

0.054

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(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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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