6-32038481-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_000500.9(CYP21A2):​c.59G>A​(p.Trp20*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Failed GnomAD Quality Control

Consequence

CYP21A2
NM_000500.9 stop_gained

Scores

3
3
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.74
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 106 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-32038481-G-A is Pathogenic according to our data. Variant chr6-32038481-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 3254748.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
CYP21A2NM_000500.9 linkuse as main transcriptc.59G>A p.Trp20* stop_gained 1/10 ENST00000644719.2 NP_000491.4 P08686Q16874Q08AG9
CYP21A2NM_001128590.4 linkuse as main transcriptc.59G>A p.Trp20* stop_gained 1/9 NP_001122062.3 P08686Q08AG9
CYP21A2NM_001368143.2 linkuse as main transcriptc.-366G>A 5_prime_UTR_variant 1/10 NP_001355072.1
CYP21A2NM_001368144.2 linkuse as main transcriptc.-276G>A 5_prime_UTR_variant 1/9 NP_001355073.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
CYP21A2ENST00000644719.2 linkuse as main transcriptc.59G>A p.Trp20* stop_gained 1/10 NM_000500.9 ENSP00000496625.1 Q16874

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152086
Hom.:
0
Cov.:
32
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:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
0.00000279
AC:
4
AN:
1434534
Hom.:
0
Cov.:
105
AF XY:
0.00000281
AC XY:
2
AN XY:
711408
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000259
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000273
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74404
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

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

Submissions by phenotype

Classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingVictorian Clinical Genetics Services, Murdoch Childrens Research InstituteJul 17, 2023Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with congenital adrenal hyperplasia due to 21-hydroxylase deficiency (MIM#201910) and nonclassic type hyperandrogenism due to 21-hydroxylase deficiency (MIM#201910). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0204 - Variant is predicted to result in a truncated protein (premature termination codon is located within the first 102 nucleotides of the coding sequence and is predicted to escape nonsense-mediated decay). (SP) 0251 - This variant is heterozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: c.59G>A with 1 heterozygote, 0 homozygotes; c.60G>A with 3 heterozygotes, 0 homozygotes). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This nucleotide change and c.60G>A, both predicted to result in p.(Trp20*), have been reported in multiple unrelated individuals with congenital adrenal hyperplasia (PMIDs: 27185867, 30048636, 30816000), and have been reported as pathogenic by a clinical laboratory (ClinVar). Both nucleotide changes have been listed as pathogenic in the EMQN guideline for molecular genetic testing and reporting of 21-hydroxylase deficiency (PMID: 32616876). c.59G>A has also been reported as in cis with p.(Val282Leu) although that is uncommon (PMID: 27185867). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.56
CADD
Pathogenic
36
DANN
Uncertain
0.99
Eigen
Pathogenic
0.82
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Uncertain
0.78
D
Vest4
0.69
GERP RS
4.5

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: rs72552743; hg19: chr6-32006258; API