chr6-32039172-C-T

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

3
13

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

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
CYP21A2NM_000500.9 linkc.371C>T p.Thr124Ile missense_variant Exon 3 of 10 ENST00000644719.2 NP_000491.4 P08686Q16874Q08AG9
CYP21A2NM_001128590.4 linkc.281C>T p.Thr94Ile missense_variant Exon 2 of 9 NP_001122062.3 P08686Q08AG9
CYP21A2NM_001368143.2 linkc.-35C>T 5_prime_UTR_variant Exon 3 of 10 NP_001355072.1
CYP21A2NM_001368144.2 linkc.-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
CYP21A2ENST00000644719.2 linkc.371C>T p.Thr124Ile missense_variant Exon 3 of 10 NM_000500.9 ENSP00000496625.1 Q16874

Frequencies

GnomAD3 genomes
AF:
0.000230
AC:
35
AN:
152036
Hom.:
1
Cov.:
31
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.:
4
Cov.:
75
AF XY:
0.000122
AC XY:
88
AN XY:
722962
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33376
American (AMR)
AF:
0.00
AC:
0
AN:
43888
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25942
East Asian (EAS)
AF:
0.00276
AC:
109
AN:
39474
South Asian (SAS)
AF:
0.000318
AC:
27
AN:
84928
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5678
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1108884
Other (OTH)
AF:
0.000316
AC:
19
AN:
60102
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.471
Heterozygous variant carriers
0
15
29
44
58
73
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
10
20
30
40
50
<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:
33
AN:
152154
Hom.:
1
Cov.:
31
AF XY:
0.000309
AC XY:
23
AN XY:
74372
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41530
American (AMR)
AF:
0.00
AC:
0
AN:
15286
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00544
AC:
28
AN:
5150
South Asian (SAS)
AF:
0.00104
AC:
5
AN:
4814
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67984
Other (OTH)
AF:
0.00
AC:
0
AN:
2106
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.499
Heterozygous variant carriers
0
2
4
6
8
10
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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.:
0
Bravo
AF:
0.000234
ExAC
AF:
0.000643
AC:
78

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
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
21
DANN
Uncertain
1.0
DEOGEN2
Benign
0.022
.;.;.;T;.;.
Eigen
Benign
0.030
Eigen_PC
Benign
-0.080
FATHMM_MKL
Benign
0.079
N
LIST_S2
Uncertain
0.89
.;.;D;D;.;.
MetaRNN
Benign
0.012
T;T;T;T;T;T
MetaSVM
Benign
-0.87
T
PhyloP100
1.5
PrimateAI
Benign
0.46
T
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
T
GERP RS
3.8
gMVP
0.47
Mutation Taster
=50/50

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

Other links and lift over

dbSNP: rs566065375; hg19: chr6-32006949; API