rs775128501
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000497.4(CYP11B1):c.841_842insACAGTACACCA(p.Ser281AsnfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 34)
Exomes 𝑓: 0.0000021 ( 0 hom. )
Consequence
CYP11B1
NM_000497.4 frameshift
NM_000497.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.908
Genes affected
CYP11B1 (HGNC:2591): (cytochrome P450 family 11 subfamily B member 1) 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 mitochondrial inner membrane and is involved in the conversion of progesterone to cortisol in the adrenal cortex. Mutations in this gene cause congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. Transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]
GML (HGNC:4375): (glycosylphosphatidylinositol anchored molecule like) Predicted to be involved in DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest; apoptotic process; and negative regulation of cell population proliferation. Predicted to be extrinsic component of membrane. [provided by Alliance of Genome Resources, Apr 2022]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 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 8-142876353-C-CTGGTGTACTGT is Pathogenic according to our data. Variant chr8-142876353-C-CTGGTGTACTGT is described in ClinVar as [Likely_pathogenic]. Clinvar id is 447227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP11B1 | NM_000497.4 | c.841_842insACAGTACACCA | p.Ser281AsnfsTer19 | frameshift_variant | 5/9 | ENST00000292427.10 | |
CYP11B1 | NM_001026213.1 | c.841_842insACAGTACACCA | p.Ser281AsnfsTer19 | frameshift_variant | 5/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP11B1 | ENST00000292427.10 | c.841_842insACAGTACACCA | p.Ser281AsnfsTer19 | frameshift_variant | 5/9 | 1 | NM_000497.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 34
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251254Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135798
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GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461828Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2AN XY: 727204
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GnomAD4 genome ? Cov.: 34
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Aug 09, 2023 | This sequence change creates a premature translational stop signal (p.Ser281Asnfs*19) in the CYP11B1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP11B1 are known to be pathogenic (PMID: 8506298, 26476331). This variant is present in population databases (rs775128501, gnomAD 0.009%). This premature translational stop signal has been observed in individual(s) with congenital adrenal hyperplasia (PMID: 24334966). This variant is also known as 3467^3468insACAGTACACCA. ClinVar contains an entry for this variant (Variation ID: 447227). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Athena Diagnostics | Sep 22, 2016 | - - |
Deficiency of steroid 11-beta-monooxygenase Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Aug 25, 2017 | - - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at