rs4545

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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:8

Conservation

PhyloP100: -1.72

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 made for transcript

Verdict is Benign. Variant got -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 id 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/exons	MANE	UniProt
CYP11B2	NM_000498.3 linkuse as main transcript	c.1303G>A	p.Gly435Ser	missense_variant	8/9	ENST00000323110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP11B2	ENST00000323110.2 linkuse as main transcript	c.1303G>A	p.Gly435Ser	missense_variant	8/9	1	NM_000498.3	P1
GML	ENST00000522728.5 linkuse as main transcript	c.182-1338C>T		intron_variant		3

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

GnomAD3 exomes

AF:

0.0918

AC:

23095

AN:

251444

Hom.:

3173

AF XY:

0.0892

AC XY:

12120

AN XY:

135916

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 SAS exome

AF:

0.147

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

Gnomad4 AFR exome

AF:

0.0230

Gnomad4 AMR exome

AF:

0.133

Gnomad4 ASJ exome

AF:

0.0321

Gnomad4 EAS exome

AF:

0.503

Gnomad4 SAS exome

AF:

0.146

Gnomad4 FIN exome

AF:

0.0508

Gnomad4 NFE exome

AF:

0.0176

Gnomad4 OTH exome

AF:

0.0589

GnomAD4 genome

AF:

0.0542

AC:

8251

AN:

152302

Hom.:

875

Cov.:

AF XY:

0.0614

AC XY:

4572

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0275

Gnomad4 AMR

AF:

0.109

Gnomad4 ASJ

AF:

0.0369

Gnomad4 EAS

AF:

0.497

Gnomad4 SAS

AF:

0.156

Gnomad4 FIN

AF:

0.0493

Gnomad4 NFE

AF:

0.0197

Gnomad4 OTH

AF:

0.0587

Alfa

AF:

0.0260

Hom.:

121

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Corticosterone methyloxidase type 2 deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Corticosterone 18-monooxygenase deficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

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% -

Corticosterone methyl oxidase type II deficiency

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Glucocorticoid-remediable aldosteronism

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.75

BayesDel_noAF

Benign

-0.70

Cadd

Benign

0.97

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

MutationTaster

Benign

1.0

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

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over