NM_000498.3:c.873G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000498.3(CYP11B2):c.873G>A(p.Ala291Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.952 in 1,613,702 control chromosomes in the GnomAD database, including 737,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.94 ( 67590 hom., cov: 32)

Exomes 𝑓: 0.95 ( 670311 hom. )

Consequence

CYP11B2
NM_000498.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -5.37

Publications

31 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 8-142914345-C-T is Benign according to our data. Variant chr8-142914345-C-T is described in ClinVar as Benign. ClinVar VariationId is 362207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-5.37 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11B2	NM_000498.3 link	c.873G>A	p.Ala291Ala	synonymous_variant	Exon 5 of 9	ENST00000323110.2	NP_000489.3	P19099

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP11B2	ENST00000323110.2 link	c.873G>A	p.Ala291Ala	synonymous_variant	Exon 5 of 9	1	NM_000498.3	ENSP00000325822.2		P19099
GML	ENST00000522728.5 link	c.264+300C>T		intron_variant	Intron 4 of 4	3		ENSP00000430799.1		E5RI31

Frequencies

GnomAD3 genomes

AF:

0.938

AC:

142591

AN:

152082

Hom.:

67546

Cov.:

show subpopulations

Gnomad AFR

AF:

0.947

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.889

Gnomad ASJ

AF:

0.963

Gnomad EAS

AF:

0.482

Gnomad SAS

AF:

0.838

Gnomad FIN

AF:

0.950

Gnomad MID

AF:

0.981

Gnomad NFE

AF:

0.980

Gnomad OTH

AF:

0.935

GnomAD2 exomes

AF:

0.905

AC:

227291

AN:

251258

AF XY:

0.908

show subpopulations

Gnomad AFR exome

AF:

0.946

Gnomad AMR exome

AF:

0.858

Gnomad ASJ exome

AF:

0.967

Gnomad EAS exome

AF:

0.477

Gnomad FIN exome

AF:

0.947

Gnomad NFE exome

AF:

0.981

Gnomad OTH exome

AF:

0.935

GnomAD4 exome

AF:

0.954

AC:

1393549

AN:

1461502

Hom.:

670311

Cov.:

AF XY:

0.951

AC XY:

691593

AN XY:

727074

show subpopulations

African (AFR)

AF:

0.951

AC:

31826

AN:

33462

American (AMR)

AF:

0.864

AC:

38619

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.968

AC:

25293

AN:

26132

East Asian (EAS)

AF:

0.487

AC:

19331

AN:

39678

South Asian (SAS)

AF:

0.855

AC:

73683

AN:

86224

European-Finnish (FIN)

AF:

0.949

AC:

50680

AN:

53416

Middle Eastern (MID)

AF:

0.966

AC:

5574

AN:

5768

European-Non Finnish (NFE)

AF:

0.982

AC:

1092019

AN:

1111732

Other (OTH)

AF:

0.936

AC:

56524

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

3514

7029

10543

14058

17572

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21564

43128

64692

86256

107820

<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:

0.938

AC:

142691

AN:

152200

Hom.:

67590

Cov.:

AF XY:

0.931

AC XY:

69225

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.947

AC:

39317

AN:

41522

American (AMR)

AF:

0.889

AC:

13584

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.963

AC:

3340

AN:

3470

East Asian (EAS)

AF:

0.481

AC:

2468

AN:

5130

South Asian (SAS)

AF:

0.839

AC:

4045

AN:

4824

European-Finnish (FIN)

AF:

0.950

AC:

10082

AN:

10608

Middle Eastern (MID)

AF:

0.980

AC:

288

AN:

294

European-Non Finnish (NFE)

AF:

0.980

AC:

66679

AN:

68036

Other (OTH)

AF:

0.934

AC:

1976

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

386

772

1159

1545

1931

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

902

1804

2706

3608

4510

<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:

0.955

Hom.:

41722

Bravo

AF:

0.935

Asia WGS

AF:

0.699

AC:

2435

AN:

3478

EpiCase

AF:

0.985

EpiControl

AF:

0.984

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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.Ala291Ala in exon 5 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 97.79% (65226/6669 8) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs4536). -

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

- -

not provided

Benign:3

Jan 18, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

Corticosterone methyloxidase type 2 deficiency

Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

Corticosterone 18-monooxygenase deficiency

Benign:2

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2018

Illumina Laboratory Services, Illumina

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 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.023

(source)

DANN

Benign

0.63

PhyloP100

-5.4

Mutation Taster

=100/0

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