rs4545

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000498.3(CYP11B2):c.1303G>A(p.Gly435Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0461 in 1,614,188 control chromosomes in the GnomAD database, including 8,072 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. Synonymous variant affecting the same amino acid position (i.e. G435G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.054 ( 875 hom., cov: 32)

Exomes 𝑓: 0.045 ( 7197 hom. )

Consequence

CYP11B2
NM_000498.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.72

Publications

37 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.875816E-5).

BP6

Variant 8-142912625-C-T is Benign according to our data. Variant chr8-142912625-C-T is described in ClinVar as Benign. ClinVar VariationId is 362192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11B2	NM_000498.3 link	c.1303G>A	p.Gly435Ser	missense_variant	Exon 8 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.1303G>A	p.Gly435Ser	missense_variant	Exon 8 of 9	1	NM_000498.3	ENSP00000325822.2
GML	ENST00000522728.5 link	c.182-1338C>T		intron_variant	Intron 3 of 4	3		ENSP00000430799.1

Frequencies

GnomAD3 genomes

AF:

0.0541

AC:

8233

AN:

152182

Hom.:

871

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0275

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.109

Gnomad ASJ

AF:

0.0369

Gnomad EAS

AF:

0.496

Gnomad SAS

AF:

0.156

Gnomad FIN

AF:

0.0493

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0196

Gnomad OTH

AF:

0.0574

GnomAD2 exomes

AF:

0.0918

AC:

23095

AN:

251444

AF XY:

0.0892

show subpopulations

Gnomad AFR exome

AF:

0.0271

Gnomad AMR exome

AF:

0.139

Gnomad ASJ exome

AF:

0.0333

Gnomad EAS exome

AF:

0.505

Gnomad FIN exome

AF:

0.0529

Gnomad NFE exome

AF:

0.0192

Gnomad OTH exome

AF:

0.0626

GnomAD4 exome

AF:

0.0453

AC:

66194

AN:

1461886

Hom.:

7197

Cov.:

AF XY:

0.0478

AC XY:

34750

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.0230

AC:

770

AN:

33480

American (AMR)

AF:

0.133

AC:

5952

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0321

AC:

838

AN:

26136

East Asian (EAS)

AF:

0.503

AC:

19976

AN:

39700

South Asian (SAS)

AF:

0.146

AC:

12573

AN:

86258

European-Finnish (FIN)

AF:

0.0508

AC:

2716

AN:

53420

Middle Eastern (MID)

AF:

0.0324

AC:

187

AN:

5768

European-Non Finnish (NFE)

AF:

0.0176

AC:

19622

AN:

1112006

Other (OTH)

AF:

0.0589

AC:

3560

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

4115

8231

12346

16462

20577

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1108

2216

3324

4432

5540

<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:

0.0542

AC:

8251

AN:

152302

Hom.:

875

Cov.:

AF XY:

0.0614

AC XY:

4572

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0275

AC:

1143

AN:

41576

American (AMR)

AF:

0.109

AC:

1674

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0369

AC:

128

AN:

3472

East Asian (EAS)

AF:

0.497

AC:

2561

AN:

5156

South Asian (SAS)

AF:

0.156

AC:

754

AN:

4830

European-Finnish (FIN)

AF:

0.0493

AC:

524

AN:

10622

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0197

AC:

1337

AN:

68026

Other (OTH)

AF:

0.0587

AC:

124

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

345

690

1036

1381

1726

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

192

288

384

480

<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:

0.0353

Hom.:

1371

Bravo

AF:

0.0561

TwinsUK

AF:

0.0146

AC:

ALSPAC

AF:

0.0202

AC:

ESP6500AA

AF:

0.0256

AC:

113

ESP6500EA

AF:

0.0207

AC:

178

ExAC

AF:

0.0871

AC:

10576

Asia WGS

AF:

0.273

AC:

948

AN:

3478

EpiCase

AF:

0.0147

EpiControl

AF:

0.0160

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Corticosterone methyloxidase type 2 deficiency

Benign:2

Mar 06, 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

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not provided

Benign:2

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 methyl oxidase type II deficiency

Benign:1

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 291/13006=2.28% -

Glucocorticoid-remediable aldosteronism

Benign:1

Mar 06, 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

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

CADD

Benign

0.97

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.081

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.60

MetaRNN

Benign

0.000099

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.23

PhyloP100

-1.7

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.65

REVEL

Benign

0.18

Sift

Benign

0.43

Sift4G

Benign

0.56

Polyphen

0.10

Vest4

0.044

MPC

0.24

ClinPred

0.00069

GERP RS

-5.9

Varity_R

0.089

gMVP

0.62

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