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GeneBe

rs6467

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000500.9(CYP21A2):c.293-13C>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.609 in 151,196 control chromosomes in the GnomAD database, including 28,032 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.61 ( 28032 hom., cov: 29)
Exomes 𝑓: 0.60 ( 254518 hom. )
Failed GnomAD Quality Control

Consequence

CYP21A2
NM_000500.9 splice_polypyrimidine_tract, intron

Scores

1
13

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.233
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=1.7294652E-6).
BP6
Variant 6-32039081-C-A is Benign according to our data. Variant chr6-32039081-C-A is described in ClinVar as [Benign]. Clinvar id is 196278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-32039081-C-A is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYP21A2NM_000500.9 linkuse as main transcriptc.293-13C>A splice_polypyrimidine_tract_variant, intron_variant ENST00000644719.2
CYP21A2NM_001368143.2 linkuse as main transcriptc.-126C>A 5_prime_UTR_variant 3/10
CYP21A2NM_001368144.2 linkuse as main transcriptc.-126C>A 5_prime_UTR_variant 2/9
CYP21A2NM_001128590.4 linkuse as main transcriptc.203-13C>A splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP21A2ENST00000644719.2 linkuse as main transcriptc.293-13C>A splice_polypyrimidine_tract_variant, intron_variant NM_000500.9 P1

Frequencies

GnomAD3 genomes
AF:
0.609
AC:
91969
AN:
151080
Hom.:
28000
Cov.:
29
show subpopulations
Gnomad AFR
AF:
0.637
Gnomad AMI
AF:
0.639
Gnomad AMR
AF:
0.711
Gnomad ASJ
AF:
0.636
Gnomad EAS
AF:
0.631
Gnomad SAS
AF:
0.596
Gnomad FIN
AF:
0.436
Gnomad MID
AF:
0.621
Gnomad NFE
AF:
0.592
Gnomad OTH
AF:
0.644
GnomAD3 exomes
AF:
0.637
AC:
141158
AN:
221616
Hom.:
44741
AF XY:
0.635
AC XY:
75748
AN XY:
119232
show subpopulations
Gnomad AFR exome
AF:
0.675
Gnomad AMR exome
AF:
0.739
Gnomad ASJ exome
AF:
0.659
Gnomad EAS exome
AF:
0.634
Gnomad SAS exome
AF:
0.629
Gnomad FIN exome
AF:
0.475
Gnomad NFE exome
AF:
0.630
Gnomad OTH exome
AF:
0.644
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.595
AC:
857154
AN:
1440498
Hom.:
254518
Cov.:
74
AF XY:
0.596
AC XY:
425953
AN XY:
714448
show subpopulations
Gnomad4 AFR exome
AF:
0.644
Gnomad4 AMR exome
AF:
0.733
Gnomad4 ASJ exome
AF:
0.647
Gnomad4 EAS exome
AF:
0.658
Gnomad4 SAS exome
AF:
0.616
Gnomad4 FIN exome
AF:
0.471
Gnomad4 NFE exome
AF:
0.588
Gnomad4 OTH exome
AF:
0.601
GnomAD4 genome
AF:
0.609
AC:
92050
AN:
151196
Hom.:
28032
Cov.:
29
AF XY:
0.605
AC XY:
44652
AN XY:
73832
show subpopulations
Gnomad4 AFR
AF:
0.636
Gnomad4 AMR
AF:
0.711
Gnomad4 ASJ
AF:
0.636
Gnomad4 EAS
AF:
0.632
Gnomad4 SAS
AF:
0.597
Gnomad4 FIN
AF:
0.436
Gnomad4 NFE
AF:
0.592
Gnomad4 OTH
AF:
0.646
Alfa
AF:
0.561
Hom.:
9188
Bravo
AF:
0.636
TwinsUK
AF:
0.614
AC:
2275
ALSPAC
AF:
0.607
AC:
2338
ESP6500AA
AF:
0.656
AC:
2883
ESP6500EA
AF:
0.616
AC:
5296
ExAC
AF:
0.608
AC:
73208

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)Sep 23, 2014- -
Benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Benign, no assertion criteria providedclinical testingDiagnostic Laboratory, Department of Genetics, University Medical Center Groningen-- -
not provided Benign:2
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Benign, criteria provided, single submitterclinical testingGeneDxFeb 15, 2019- -
Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabMay 12, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.64
T
BayesDel_noAF
Benign
-0.54
CADD
Benign
2.0
DANN
Benign
0.44
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.4
FATHMM_MKL
Benign
0.0018
N
LIST_S2
Benign
0.23
T
MetaRNN
Benign
0.0000017
T
MetaSVM
Benign
-1.0
T
MutationTaster
Benign
1.0
P;P
PROVEAN
Benign
0.40
N
REVEL
Benign
0.034
Sift
Benign
0.31
T
Sift4G
Pathogenic
0.0
D
ClinPred
0.0018
T
GERP RS
-0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs6467; hg19: chr6-32006858; COSMIC: COSV64479798; COSMIC: COSV64479798; API