NM_000498.3:c.504C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000498.3(CYP11B2):​c.504C>T​(p.Phe168Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 1,612,206 control chromosomes in the GnomAD database, including 157,026 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.39 ( 12172 hom., cov: 31)
Exomes 𝑓: 0.44 ( 144854 hom. )

Consequence

CYP11B2
NM_000498.3 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.58
Variant links:
Genes affected
CYP11B2 (HGNC:2592): (cytochrome P450 family 11 subfamily B 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 mitochondrial inner membrane. The enzyme has steroid 18-hydroxylase activity to synthesize aldosterone and 18-oxocortisol as well as steroid 11 beta-hydroxylase activity. Mutations in this gene cause corticosterone methyl oxidase deficiency. [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 made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.64).
BP6
Variant 8-142915137-G-A is Benign according to our data. Variant chr8-142915137-G-A is described in ClinVar as [Benign]. Clinvar id is 362221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-142915137-G-A is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=1.58 with no splicing effect.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CYP11B2NM_000498.3 linkc.504C>T p.Phe168Phe synonymous_variant Exon 3 of 9 ENST00000323110.2 NP_000489.3 P19099

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CYP11B2ENST00000323110.2 linkc.504C>T p.Phe168Phe synonymous_variant Exon 3 of 9 1 NM_000498.3 ENSP00000325822.2 P19099
GMLENST00000522728.5 linkc.264+1092G>A intron_variant Intron 4 of 4 3 ENSP00000430799.1 E5RI31

Frequencies

GnomAD3 genomes
AF:
0.385
AC:
58465
AN:
151792
Hom.:
12166
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.226
Gnomad AMI
AF:
0.520
Gnomad AMR
AF:
0.429
Gnomad ASJ
AF:
0.541
Gnomad EAS
AF:
0.298
Gnomad SAS
AF:
0.417
Gnomad FIN
AF:
0.479
Gnomad MID
AF:
0.437
Gnomad NFE
AF:
0.451
Gnomad OTH
AF:
0.418
GnomAD3 exomes
AF:
0.424
AC:
105583
AN:
248894
Hom.:
22865
AF XY:
0.431
AC XY:
58038
AN XY:
134608
show subpopulations
Gnomad AFR exome
AF:
0.224
Gnomad AMR exome
AF:
0.430
Gnomad ASJ exome
AF:
0.548
Gnomad EAS exome
AF:
0.292
Gnomad SAS exome
AF:
0.428
Gnomad FIN exome
AF:
0.494
Gnomad NFE exome
AF:
0.446
Gnomad OTH exome
AF:
0.442
GnomAD4 exome
AF:
0.443
AC:
646392
AN:
1460298
Hom.:
144854
Cov.:
49
AF XY:
0.443
AC XY:
322145
AN XY:
726432
show subpopulations
Gnomad4 AFR exome
AF:
0.221
Gnomad4 AMR exome
AF:
0.431
Gnomad4 ASJ exome
AF:
0.549
Gnomad4 EAS exome
AF:
0.318
Gnomad4 SAS exome
AF:
0.432
Gnomad4 FIN exome
AF:
0.498
Gnomad4 NFE exome
AF:
0.450
Gnomad4 OTH exome
AF:
0.443
GnomAD4 genome
AF:
0.385
AC:
58497
AN:
151908
Hom.:
12172
Cov.:
31
AF XY:
0.390
AC XY:
28956
AN XY:
74218
show subpopulations
Gnomad4 AFR
AF:
0.226
Gnomad4 AMR
AF:
0.429
Gnomad4 ASJ
AF:
0.541
Gnomad4 EAS
AF:
0.297
Gnomad4 SAS
AF:
0.419
Gnomad4 FIN
AF:
0.479
Gnomad4 NFE
AF:
0.451
Gnomad4 OTH
AF:
0.415
Alfa
AF:
0.427
Hom.:
5859
Bravo
AF:
0.375
Asia WGS
AF:
0.314
AC:
1093
AN:
3476
EpiCase
AF:
0.459
EpiControl
AF:
0.459

ClinVar

Significance: Benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Mar 21, 2016
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

p.Phe168Phe in exon 3 of CYP11B2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 49.56% (3052/6158) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs4546). -

not provided Benign:3
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Aug 02, 2021
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Corticosterone methyloxidase type 2 deficiency Benign:2
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 01, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Corticosterone 18-monooxygenase deficiency Benign:2
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jul 01, 2021
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Corticosterone methyl oxidase type II deficiency Benign:1
Sep 16, 2020
Natera, Inc.
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Glucocorticoid-remediable aldosteronism Benign:1
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.64
CADD
Benign
7.8
DANN
Benign
0.75

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4546; hg19: chr8-143996553; COSMIC: COSV59994442; API