8-142877196-C-T
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PP3_StrongPP5
The NM_000497.4(CYP11B1):c.422G>A(p.Arg141Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000434 in 1,613,836 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )
Consequence
CYP11B1
NM_000497.4 missense
NM_000497.4 missense
Scores
10
8
1
Clinical Significance
Conservation
PhyloP100: 5.54
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 Likely_pathogenic. Variant got 7 ACMG points.
PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000497.4
PP3
MetaRNN computational evidence supports a deleterious effect, 0.987
PP5
Variant 8-142877196-C-T is Pathogenic according to our data. Variant chr8-142877196-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 77208.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=3}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CYP11B1 | NM_000497.4 | c.422G>A | p.Arg141Gln | missense_variant | 3/9 | ENST00000292427.10 | |
CYP11B1 | NM_001026213.1 | c.422G>A | p.Arg141Gln | missense_variant | 3/8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CYP11B1 | ENST00000292427.10 | c.422G>A | p.Arg141Gln | missense_variant | 3/9 | 1 | NM_000497.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000399 AC: 1AN: 250542Hom.: 0 AF XY: 0.00000738 AC XY: 1AN XY: 135432
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GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461644Hom.: 0 Cov.: 40 AF XY: 0.00000688 AC XY: 5AN XY: 727082
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152192Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74338
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:3Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Feb 22, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 12, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 141 of the CYP11B1 protein (p.Arg141Gln). This variant is present in population databases (rs267601810, gnomAD 0.003%). This missense change has been observed in individuals with 11-beta-hydroxylase deficiency (PMID: 24987415, 26956189). ClinVar contains an entry for this variant (Variation ID: 77208). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP11B1 protein function with a positive predictive value of 95%. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Deficiency of steroid 11-beta-monooxygenase Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Apr 04, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 18, 2023 | - - |
CYP11B1-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 11, 2023 | The CYP11B1 c.422G>A variant is predicted to result in the amino acid substitution p.Arg141Gln. This variant has been reported in a compound heterozygous state with another variant in individuals with 11 beta-hydroxylase deficiency (Dumic et al. 2014. PubMed ID: 24987415; Table S1 - Khattab et al. 2017. PubMed ID: 28228528). This variant was also reported with another novel variant in an individual with 11 beta-hydroxylase deficiency (Kandemir et al. 2017. PubMed ID: 26956189). This variant is reported in 0.0033% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/8-143958612-C-T). This variant falls within a highly paralogous region. Allele frequency data should be interpreted with caution. This variant is interpreted as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
M;M;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;D
Vest4
MutPred
0.88
.;.;Loss of MoRF binding (P = 0.0663);
MVP
MPC
ClinPred
D
GERP RS
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gMVP
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at