rs4544

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000498.3(CYP11B2):c.1016T>C(p.Ile339Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0314 in 1,613,748 control chromosomes in the GnomAD database, including 6,525 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I339N) has been classified as Benign.

Frequency

Genomes: 𝑓 0.12 ( 3327 hom., cov: 32)

Exomes 𝑓: 0.022 ( 3198 hom. )

Consequence

CYP11B2
NM_000498.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.599

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=0.018127918).

BP6

Variant 8-142913390-A-G is Benign according to our data. Variant chr8-142913390-A-G is described in ClinVar as [Benign]. Clinvar id is 362201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.388 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.1016T>C	p.Ile339Thr	missense_variant	6/9	ENST00000323110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP11B2	ENST00000323110.2 linkuse as main transcript	c.1016T>C	p.Ile339Thr	missense_variant	6/9	1	NM_000498.3	P1
GML	ENST00000522728.5 linkuse as main transcript	c.182-573A>G		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.121

AC:

18396

AN:

151976

Hom.:

3299

Cov.:

show subpopulations

Gnomad AFR

AF:

0.392

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0585

Gnomad ASJ

AF:

0.00778

Gnomad EAS

AF:

0.0221

Gnomad SAS

AF:

0.0614

Gnomad FIN

AF:

0.00518

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.00844

Gnomad OTH

AF:

0.101

GnomAD3 exomes

AF:

0.0455

AC:

11401

AN:

250774

Hom.:

1428

AF XY:

0.0385

AC XY:

5222

AN XY:

135694

show subpopulations

Gnomad AFR exome

AF:

0.398

Gnomad AMR exome

AF:

0.0438

Gnomad ASJ exome

AF:

0.00646

Gnomad EAS exome

AF:

0.0215

Gnomad SAS exome

AF:

0.0516

Gnomad FIN exome

AF:

0.00434

Gnomad NFE exome

AF:

0.00969

Gnomad OTH exome

AF:

0.0319

GnomAD4 exome

AF:

0.0221

AC:

32258

AN:

1461654

Hom.:

3198

Cov.:

AF XY:

0.0216

AC XY:

15685

AN XY:

727134

show subpopulations

Gnomad4 AFR exome

AF:

0.406

Gnomad4 AMR exome

AF:

0.0452

Gnomad4 ASJ exome

AF:

0.00723

Gnomad4 EAS exome

AF:

0.0126

Gnomad4 SAS exome

AF:

0.0490

Gnomad4 FIN exome

AF:

0.00477

Gnomad4 NFE exome

AF:

0.00801

Gnomad4 OTH exome

AF:

0.0382

GnomAD4 genome

AF:

0.121

AC:

18474

AN:

152094

Hom.:

3327

Cov.:

AF XY:

0.118

AC XY:

8742

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.393

Gnomad4 AMR

AF:

0.0583

Gnomad4 ASJ

AF:

0.00778

Gnomad4 EAS

AF:

0.0221

Gnomad4 SAS

AF:

0.0614

Gnomad4 FIN

AF:

0.00518

Gnomad4 NFE

AF:

0.00843

Gnomad4 OTH

AF:

0.100

Alfa

AF:

0.0184

Hom.:

453

Bravo

AF:

0.136

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.378

AC:

1665

ESP6500EA

AF:

0.00640

AC:

ExAC

AF:

0.0524

AC:

6364

EpiCase

AF:

0.0111

EpiControl

AF:

0.0107

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Corticosterone methyl oxidase type II deficiency

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Nov 22, 2019

- -

Corticosterone methyloxidase type 2 deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Corticosterone 18-monooxygenase deficiency

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

Jan 13, 2018

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.87

DEOGEN2

Benign

0.081

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.89

FATHMM_MKL

Benign

0.0099

LIST_S2

Benign

0.062

MetaRNN

Benign

0.018

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.55

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.62

PROVEAN

Benign

1.3

REVEL

Benign

0.089

Sift

Benign

0.12

Sift4G

Benign

0.44

Polyphen

0.0

Vest4

0.024

MPC

0.29

ClinPred

0.0013

GERP RS

3.7

Varity_R

0.18

gMVP

0.70

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