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GeneBe

rs9378251

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PM5PP3_StrongPP5_Moderate

The NM_000500.9(CYP21A2):c.92C>A(p.Pro31Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P31L) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

CYP21A2
NM_000500.9 missense

Scores

2
11
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.34
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 Pathogenic. Variant got 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr6-32038514-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 12153.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.979
PP5
Variant 6-32038514-C-A is Pathogenic according to our data. Variant chr6-32038514-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 988330.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CYP21A2NM_000500.9 linkuse as main transcriptc.92C>A p.Pro31Gln missense_variant 1/10 ENST00000644719.2
CYP21A2NM_001128590.4 linkuse as main transcriptc.92C>A p.Pro31Gln missense_variant 1/9
CYP21A2NM_001368143.2 linkuse as main transcriptc.-333C>A 5_prime_UTR_variant 1/10
CYP21A2NM_001368144.2 linkuse as main transcriptc.-243C>A 5_prime_UTR_variant 1/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CYP21A2ENST00000644719.2 linkuse as main transcriptc.92C>A p.Pro31Gln missense_variant 1/10 NM_000500.9 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
107
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingClinical Genetics and Genomics, Karolinska University HospitalNov 23, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
Cadd
Uncertain
25
Dann
Uncertain
0.99
Eigen
Uncertain
0.41
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Uncertain
0.79
D
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Uncertain
0.066
D
MutationTaster
Benign
0.56
D;D
PrimateAI
Benign
0.48
T
PROVEAN
Uncertain
-3.4
D;.;D;D;D;.
REVEL
Uncertain
0.58
Sift
Uncertain
0.024
D;.;D;D;D;.
Sift4G
Uncertain
0.0040
D;.;D;D;D;.
Polyphen
1.0
D;D;.;.;.;D
Vest4
0.85
MutPred
0.94
Gain of MoRF binding (P = 0.055);Gain of MoRF binding (P = 0.055);Gain of MoRF binding (P = 0.055);Gain of MoRF binding (P = 0.055);Gain of MoRF binding (P = 0.055);Gain of MoRF binding (P = 0.055);
MVP
0.93
MPC
3.3
ClinPred
0.95
D
GERP RS
3.6
gMVP
0.73

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

LitVar

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

Other links and lift over

dbSNP: rs9378251; hg19: chr6-32006291; API