rs4539

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000498.3(CYP11B2):c.518A>G(p.Lys173Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 151,876 control chromosomes in the GnomAD database, including 12,203 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.39 ( 12203 hom., cov: 31)

Exomes 𝑓: 0.44 ( 144826 hom. )

Failed GnomAD Quality Control

Consequence

CYP11B2
NM_000498.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: -0.530

Publications

63 publications found

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]

CYP11B2 links:

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]

GML links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 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, 8 uncertain in NM_000498.3

BP4

Computational evidence support a benign effect (MetaRNN=3.9825718E-5).

BP6

Variant 8-142915123-T-C is Benign according to our data. Variant chr8-142915123-T-C is described in ClinVar as Benign. ClinVar VariationId is 362220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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
CYP11B2	NM_000498.3 link	c.518A>G	p.Lys173Arg	missense_variant	Exon 3 of 9	ENST00000323110.2	NP_000489.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP11B2	ENST00000323110.2 link	c.518A>G	p.Lys173Arg	missense_variant	Exon 3 of 9	1	NM_000498.3	ENSP00000325822.2
GML	ENST00000522728.5 link	c.264+1078T>C		intron_variant	Intron 4 of 4	3		ENSP00000430799.1

Frequencies

GnomAD3 genomes

AF:

0.386

AC:

58596

AN:

151760

Hom.:

12195

Cov.:

show subpopulations

Gnomad AFR

AF:

0.229

Gnomad AMI

AF:

0.520

Gnomad AMR

AF:

0.430

Gnomad ASJ

AF:

0.541

Gnomad EAS

AF:

0.298

Gnomad SAS

AF:

0.418

Gnomad FIN

AF:

0.480

Gnomad MID

AF:

0.440

Gnomad NFE

AF:

0.451

Gnomad OTH

AF:

0.420

GnomAD2 exomes

AF:

0.424

AC:

105290

AN:

248332

AF XY:

0.431

show subpopulations

Gnomad AFR exome

AF:

0.227

Gnomad AMR exome

AF:

0.430

Gnomad ASJ exome

AF:

0.548

Gnomad EAS exome

AF:

0.291

Gnomad FIN exome

AF:

0.493

Gnomad NFE exome

AF:

0.446

Gnomad OTH exome

AF:

0.443

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.443

AC:

646367

AN:

1459998

Hom.:

144826

Cov.:

AF XY:

0.444

AC XY:

322074

AN XY:

726180

show subpopulations

African (AFR)

AF:

0.224

AC:

7511

AN:

33464

American (AMR)

AF:

0.431

AC:

19173

AN:

44520

Ashkenazi Jewish (ASJ)

AF:

0.549

AC:

14342

AN:

26116

East Asian (EAS)

AF:

0.318

AC:

12601

AN:

39674

South Asian (SAS)

AF:

0.432

AC:

37175

AN:

86068

European-Finnish (FIN)

AF:

0.498

AC:

26524

AN:

53314

Middle Eastern (MID)

AF:

0.470

AC:

2706

AN:

5752

European-Non Finnish (NFE)

AF:

0.450

AC:

499602

AN:

1110756

Other (OTH)

AF:

0.443

AC:

26733

AN:

60334

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

22097

44193

66290

88386

110483

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

14968

29936

44904

59872

74840

<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

AF:

0.386

AC:

58630

AN:

151876

Hom.:

12203

Cov.:

AF XY:

0.391

AC XY:

29016

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.229

AC:

9507

AN:

41482

American (AMR)

AF:

0.430

AC:

6559

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.541

AC:

1877

AN:

3468

East Asian (EAS)

AF:

0.297

AC:

1524

AN:

5134

South Asian (SAS)

AF:

0.420

AC:

2026

AN:

4828

European-Finnish (FIN)

AF:

0.480

AC:

5055

AN:

10526

Middle Eastern (MID)

AF:

0.428

AC:

125

AN:

292

European-Non Finnish (NFE)

AF:

0.451

AC:

30604

AN:

67862

Other (OTH)

AF:

0.417

AC:

880

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1817

3634

5451

7268

9085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

562

1124

1686

2248

2810

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.428

Hom.:

6085

Bravo

AF:

0.376

ESP6500AA

AF:

0.236

AC:

1038

ESP6500EA

AF:

0.449

AC:

3857

ExAC

AF:

0.417

AC:

50583

EpiCase

AF:

0.459

EpiControl

AF:

0.459

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

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.Lys173Arg in exon 3 of CYP11B2: This variant is not expected to have clinical significance because it has been identified in 49.39% (2973/6020) of Finnish chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs4539). -

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 8954040) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Corticosterone methyloxidase type 2 deficiency

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Corticosterone 18-monooxygenase deficiency

Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Corticosterone methyl oxidase type II deficiency

Benign:1

Aug 23, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Corticosterone 18-monooxygenase deficiency;C3463917:Corticosterone methyloxidase type 2 deficiency

Benign:1

Aug 29, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glucocorticoid-remediable aldosteronism

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.77

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.20

(source)

DANN

Benign

0.36

DEOGEN2

Benign

0.092

Eigen

Benign

-2.0

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.52

MetaRNN

Benign

0.000040

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.33

PhyloP100

-0.53

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.34

REVEL

Benign

0.035

Sift

Benign

0.62

Sift4G

Benign

0.85

Polyphen

0.0

Vest4

0.052

MPC

0.20

ClinPred

0.0081

GERP RS

-4.2

Varity_R

0.10

gMVP

0.64

Mutation Taster

=96/4

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over