chr6-32039745-G-A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_000500.9(CYP21A2):​c.652-4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000379 in 1,608,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000038 ( 0 hom. )

Consequence

CYP21A2
NM_000500.9 splice_region, intron

Scores

2
Splicing: ADA: 0.00004879
2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.227

Publications

0 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.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.64).
BP6
Variant 6-32039745-G-A is Benign according to our data. Variant chr6-32039745-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 256296.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYP21A2NM_000500.9 linkc.652-4G>A splice_region_variant, intron_variant Intron 5 of 9 ENST00000644719.2 NP_000491.4 P08686Q16874Q08AG9
CYP21A2NM_001128590.4 linkc.562-4G>A splice_region_variant, intron_variant Intron 4 of 8 NP_001122062.3 P08686Q08AG9
CYP21A2NM_001368143.2 linkc.247-4G>A splice_region_variant, intron_variant Intron 5 of 9 NP_001355072.1
CYP21A2NM_001368144.2 linkc.247-4G>A splice_region_variant, intron_variant Intron 4 of 8 NP_001355073.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYP21A2ENST00000644719.2 linkc.652-4G>A splice_region_variant, intron_variant Intron 5 of 9 NM_000500.9 ENSP00000496625.1 Q16874

Frequencies

GnomAD3 genomes
AF:
0.0000395
AC:
6
AN:
151984
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000242
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000166
AC:
4
AN:
240450
AF XY:
0.0000230
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000369
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000378
AC:
55
AN:
1456122
Hom.:
0
Cov.:
61
AF XY:
0.0000345
AC XY:
25
AN XY:
723764
show subpopulations
African (AFR)
AF:
0.0000601
AC:
2
AN:
33276
American (AMR)
AF:
0.00
AC:
0
AN:
44144
Ashkenazi Jewish (ASJ)
AF:
0.000154
AC:
4
AN:
26016
East Asian (EAS)
AF:
0.0000254
AC:
1
AN:
39376
South Asian (SAS)
AF:
0.00
AC:
0
AN:
84986
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52976
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5760
European-Non Finnish (NFE)
AF:
0.0000424
AC:
47
AN:
1109448
Other (OTH)
AF:
0.0000166
AC:
1
AN:
60140
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.478
Heterozygous variant carriers
0
4
8
13
17
21
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
4
8
12
16
20
<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:
0.0000395
AC:
6
AN:
151984
Hom.:
0
Cov.:
31
AF XY:
0.0000270
AC XY:
2
AN XY:
74210
show subpopulations
African (AFR)
AF:
0.0000242
AC:
1
AN:
41374
American (AMR)
AF:
0.00
AC:
0
AN:
15256
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5164
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4818
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10588
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000735
AC:
5
AN:
67998
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
1
1
2
2
3
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:
0.0000494
Hom.:
0
Bravo
AF:
0.0000529

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
-
PreventionGenetics, part of Exact Sciences
Significance:Likely 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
-0.64
CADD
Benign
5.5
DANN
Benign
0.67
PhyloP100
-0.23

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000049
dbscSNV1_RF
Benign
0.0040
SpliceAI score (max)
0.020
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: rs373648076; hg19: chr6-32007522; API