chr6-32039178-C-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000500.9(CYP21A2):c.377C>G(p.Ser126Ter) variant causes a stop gained 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 (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 31)
Consequence
CYP21A2
NM_000500.9 stop_gained
NM_000500.9 stop_gained
Scores
3
2
2
Clinical Significance
Conservation
PhyloP100: 2.26
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 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-32039178-C-G is Pathogenic according to our data. Variant chr6-32039178-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 375321.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-32039178-C-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP21A2 | NM_000500.9 | c.377C>G | p.Ser126Ter | stop_gained | 3/10 | ENST00000644719.2 | |
CYP21A2 | NM_001128590.4 | c.287C>G | p.Ser96Ter | stop_gained | 2/9 | ||
CYP21A2 | NM_001368143.2 | c.-29C>G | 5_prime_UTR_variant | 3/10 | |||
CYP21A2 | NM_001368144.2 | c.-29C>G | 5_prime_UTR_variant | 2/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP21A2 | ENST00000644719.2 | c.377C>G | p.Ser126Ter | stop_gained | 3/10 | NM_000500.9 | P1 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 77
GnomAD4 exome
Cov.:
77
GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
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 submitter | clinical testing | Invitae | Jun 16, 2021 | The frequency data for this variant in the population databases (ExAC) is considered unreliable due to the presence of homologous sequence, such as pseudogenes or paralogs, in the genome. For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in CYP21A2 are known to be pathogenic (PMID: 10857554). This variant has been observed in individuals with classic salt-wasting congenital adrenal hyperplasia due to 21-hydroxylase deficiency (PMID: 30048636, 31446012). ClinVar contains an entry for this variant (Variation ID: 375321). This sequence change creates a premature translational stop signal (p.Ser126*) in the CYP21A2 gene. It is expected to result in an absent or disrupted protein product. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MutationTaster
Benign
A;A
Vest4
GERP RS
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at