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rs9378251

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2_SupportingPM5PP3_StrongPP5_Moderate

The NM_000500(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 Genomes 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 missense

Scores

2
11
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.34

Links

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
?
Very rare variant; Number of alleles below threshold, Median coverage is 32.
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

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 Karolinska University Hospital, 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
24
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

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;