6-32039172-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2BP4_StrongBS2_Supporting

The NM_000500.9(CYP21A2):c.371C>T(p.Thr124Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000117 in 1,607,046 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00022 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00011 ( 4 hom. )

Consequence

CYP21A2
NM_000500.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 1.47

Publications

6 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: Likely_benign. The variant received -4 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=0.012173027).

BS2

High Homozygotes in GnomAdExome4 at 4 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.371C>T	p.Thr124Ile	missense_variant	Exon 3 of 10	ENST00000644719.2	NP_000491.4	P08686Q16874Q08AG9
CYP21A2	NM_001128590.4 link	c.281C>T	p.Thr94Ile	missense_variant	Exon 2 of 9		NP_001122062.3	P08686Q08AG9
CYP21A2	NM_001368143.2 link	c.-35C>T		5_prime_UTR_variant	Exon 3 of 10		NP_001355072.1
CYP21A2	NM_001368144.2 link	c.-35C>T		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.371C>T	p.Thr124Ile	missense_variant	Exon 3 of 10		NM_000500.9	ENSP00000496625.1		Q16874

Frequencies

GnomAD3 genomes

AF:

0.000230

AC:

AN:

152036

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00581

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000619

AC:

147

AN:

237412

AF XY:

0.000624

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00769

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000342

GnomAD4 exome

AF:

0.000107

AC:

155

AN:

1454892

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

722962

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33376

American (AMR)

AF:

0.00

AC:

AN:

43888

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25942

East Asian (EAS)

AF:

0.00276

AC:

109

AN:

39474

South Asian (SAS)

AF:

0.000318

AC:

AN:

84928

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1108884

Other (OTH)

AF:

0.000316

AC:

AN:

60102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

GnomAD4 genome

AF:

0.000217

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41530

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00544

AC:

AN:

5150

South Asian (SAS)

AF:

0.00104

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67984

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

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:

0.00

Hom.:

Bravo

AF:

0.000234

ExAC

AF:

0.000643

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency

Uncertain:2

Mar 17, 2023

Newborn Screening Ontario, Children's Hospital of Eastern Ontario (CHEO)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PM3_Strong+BP4 -

not specified

Uncertain:1

Feb 16, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: CYP21A2 c.371C>T (p.Thr124Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00062 in 237412 control chromosomes, predominantly at a frequency of 0.0077 within the East Asian subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within East Asian control individuals in the gnomAD database is higher than the estimated maximal expected allele frequency for a pathogenic variant in CYP21A2 causing severe Congenital Adrenal Hyperplasia phenotype (0.002), however the prevalence of nonclassic adrenal hyperplasia might be much higher in certain ethnic groups (see e.g. PMIDs 26082286, 29035424), therefore this frequency might not exclude that the variant is associated with disease. The variant, c.371C>T, has been reported in the literature in individuals affected with Congenital Adrenal Hyperplasia (e.g. Wang_2016, Hou_2019, Chi_2019, Hou_2020, Wan_2023), however, in at least two of these cases the variant occurred in cis with another (likely) pathogenic variant (Wang_2016, Hou_2019), or was reported without specifying a second variant (Hou_2020). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

not provided

Uncertain:1

Dec 30, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.022

.;.;.;T;.;.

Eigen

Benign

0.030

Eigen_PC

Benign

-0.080

FATHMM_MKL

Benign

0.079

LIST_S2

Uncertain

0.89

.;.;D;D;.;.

MetaRNN

Benign

0.012

T;T;T;T;T;T

MetaSVM

Benign

-0.87

PhyloP100

1.5

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.1

N;.;N;N;N;.

REVEL

Benign

0.25

Sift

Benign

0.048

D;.;D;D;D;.

Sift4G

Uncertain

0.0090

D;.;D;D;D;.

Polyphen

0.96

D;D;.;.;.;D

Vest4

0.29

MutPred

0.60

Gain of catalytic residue at L129 (P = 0.0394);Gain of catalytic residue at L129 (P = 0.0394);.;Gain of catalytic residue at L129 (P = 0.0394);.;Gain of catalytic residue at L129 (P = 0.0394);

MVP

0.77

MPC

1.2

ClinPred

0.076

GERP RS

3.8

gMVP

0.47

Mutation Taster

=50/50

(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