NM_000497.4:c.346T>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PM5PP2PP3_StrongPP5

The NM_000497.4(CYP11B1):​c.346T>G​(p.Trp116Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,892 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W116C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

CYP11B1
NM_000497.4 missense

Scores

10
7
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 3.31

Publications

3 publications found
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr8-142879079-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 1458049.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: -1.5619 (below the threshold of 3.09). Trascript score misZ: -0.26962 (below the threshold of 3.09). GenCC associations: The gene is linked to glucocorticoid-remediable aldosteronism, congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.989
PP5
Variant 8-142879081-A-C is Pathogenic according to our data. Variant chr8-142879081-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 553208.We mark this variant Likely_pathogenic, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYP11B1NM_000497.4 linkc.346T>G p.Trp116Gly missense_variant Exon 2 of 9 ENST00000292427.10 NP_000488.3 P15538-1Q8TDD0
CYP11B1NM_001026213.1 linkc.346T>G p.Trp116Gly missense_variant Exon 2 of 8 NP_001021384.1 P15538-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYP11B1ENST00000292427.10 linkc.346T>G p.Trp116Gly missense_variant Exon 2 of 9 1 NM_000497.4 ENSP00000292427.5 P15538-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.0000119
AC:
3
AN:
251450
AF XY:
0.00000736
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1461892
Hom.:
0
Cov.:
32
AF XY:
0.00000413
AC XY:
3
AN XY:
727248
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86258
European-Finnish (FIN)
AF:
0.0000187
AC:
1
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1112012
Other (OTH)
AF:
0.00
AC:
0
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.485
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
32
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Deficiency of steroid 11-beta-monooxygenase;C3838731:Glucocorticoid-remediable aldosteronism Pathogenic:1
Mar 05, 2024
Fulgent Genetics, Fulgent Genetics
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Pathogenic:1
Jun 11, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

Experimental studies have shown that this variant affects CYP11B1 protein function (PMID: 20089618). This sequence change replaces tryptophan with glycine at codon 116 of the CYP11B1 protein (p.Trp116Gly). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and glycine. This variant is present in population databases (rs772733691, ExAC 0.001%). This variant has been observed in individual(s) with adrenal hyperplasia (PMID: 20089618). ClinVar contains an entry for this variant (Variation ID: 553208). 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. This variant disrupts the p.Trp116 amino acid residue in CYP11B1. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 15755848, 18204274, 28228528). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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 Uncertain:1
Aug 07, 2017
Counsyl
Significance:Uncertain significance
Review Status:no assertion criteria provided
Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Glucocorticoid-remediable aldosteronism Uncertain:1
Apr 28, 2017
Illumina Laboratory Services, Illumina
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.82
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.23
CADD
Pathogenic
27
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.77
D;.;.
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.48
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.81
T;T;T
M_CAP
Pathogenic
0.77
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Uncertain
-0.025
T
MutationAssessor
Pathogenic
3.2
M;M;.
PhyloP100
3.3
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-12
D;D;D
REVEL
Pathogenic
0.68
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;.;D
Vest4
0.70
MutPred
0.85
.;.;Gain of disorder (P = 0.0042);
MVP
0.92
MPC
0.61
ClinPred
1.0
D
GERP RS
3.6
Varity_R
0.94
gMVP
0.66
Mutation Taster
=0/100
disease causing

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs772733691; hg19: chr8-143960497; API