rs121912977
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_000498.3(CYP11B2):c.763G>T(p.Glu255Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,612,950 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 (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000498.3 stop_gained
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP11B2 | NM_000498.3 | c.763G>T | p.Glu255Ter | stop_gained | 4/9 | ENST00000323110.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP11B2 | ENST00000323110.2 | c.763G>T | p.Glu255Ter | stop_gained | 4/9 | 1 | NM_000498.3 | P1 | |
GML | ENST00000522728.5 | c.264+696C>A | intron_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000198 AC: 3AN: 151842Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.00000801 AC: 2AN: 249626Hom.: 0 AF XY: 0.00000741 AC XY: 1AN XY: 134926
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461108Hom.: 0 Cov.: 41 AF XY: 0.0000165 AC XY: 12AN XY: 726740
GnomAD4 genome ? AF: 0.0000198 AC: 3AN: 151842Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 74182
ClinVar
Submissions by phenotype
Corticosterone methyl oxidase type II deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Corticosterone methyloxidase type 2 deficiency Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | May 22, 2022 | The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported to be associated with CYP11B2- related disorder (ClinVar ID: VCV000016880). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Corticosterone 18-monooxygenase deficiency Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 01, 2004 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 01, 2023 | This sequence change creates a premature translational stop signal (p.Glu255*) in the CYP11B2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CYP11B2 are known to be pathogenic (PMID: 20494601, 22801770, 26936515). This variant is present in population databases (rs121912977, gnomAD 0.0009%). This premature translational stop signal has been observed in individual(s) with aldosterone synthase deficiency (PMID: 9703385, 15240589). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 16880). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at