NM_000498.3:c.1120C>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.1120C>A(p.Arg374Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,610,144 control chromosomes in the GnomAD database, including 263,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R374R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.55 ( 23124 hom., cov: 29)

Exomes 𝑓: 0.57 ( 239974 hom. )

Consequence

CYP11B2
NM_000498.3 splice_region, synonymous

Scores

Splicing: ADA: 0.0001083

Clinical Significance

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

Conservation

PhyloP100: 1.01

Publications

24 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=-0.6).

BP6

Variant 8-142913286-G-T is Benign according to our data. Variant chr8-142913286-G-T is described in ClinVar as Benign. ClinVar VariationId is 362195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.01 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11B2	NM_000498.3 link	c.1120C>A	p.Arg374Arg	splice_region_variant, synonymous_variant	Exon 6 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.1120C>A	p.Arg374Arg	splice_region_variant, synonymous_variant	Exon 6 of 9	1	NM_000498.3	ENSP00000325822.2		P19099
GML	ENST00000522728.5 link	c.182-677G>T		intron_variant	Intron 3 of 4	3		ENSP00000430799.1		E5RI31

Frequencies

GnomAD3 genomes

AF:

0.554

AC:

82848

AN:

149446

Hom.:

23113

Cov.:

show subpopulations

Gnomad AFR

AF:

0.476

Gnomad AMI

AF:

0.552

Gnomad AMR

AF:

0.597

Gnomad ASJ

AF:

0.641

Gnomad EAS

AF:

0.800

Gnomad SAS

AF:

0.651

Gnomad FIN

AF:

0.599

Gnomad MID

AF:

0.627

Gnomad NFE

AF:

0.554

Gnomad OTH

AF:

0.581

GnomAD2 exomes

AF:

0.600

AC:

148144

AN:

247034

AF XY:

0.603

show subpopulations

Gnomad AFR exome

AF:

0.488

Gnomad AMR exome

AF:

0.608

Gnomad ASJ exome

AF:

0.643

Gnomad EAS exome

AF:

0.805

Gnomad FIN exome

AF:

0.620

Gnomad NFE exome

AF:

0.556

Gnomad OTH exome

AF:

0.588

GnomAD4 exome

AF:

0.571

AC:

833445

AN:

1460576

Hom.:

239974

Cov.:

AF XY:

0.574

AC XY:

417045

AN XY:

726610

show subpopulations

African (AFR)

AF:

0.484

AC:

16192

AN:

33450

American (AMR)

AF:

0.604

AC:

26969

AN:

44682

Ashkenazi Jewish (ASJ)

AF:

0.645

AC:

16851

AN:

26114

East Asian (EAS)

AF:

0.808

AC:

32059

AN:

39682

South Asian (SAS)

AF:

0.664

AC:

57246

AN:

86222

European-Finnish (FIN)

AF:

0.616

AC:

32468

AN:

52702

Middle Eastern (MID)

AF:

0.643

AC:

3690

AN:

5740

European-Non Finnish (NFE)

AF:

0.551

AC:

612666

AN:

1111640

Other (OTH)

AF:

0.585

AC:

35304

AN:

60344

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

21323

42646

63968

85291

106614

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17384

34768

52152

69536

86920

<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:

0.554

AC:

82890

AN:

149568

Hom.:

23124

Cov.:

AF XY:

0.562

AC XY:

41032

AN XY:

72974

show subpopulations

African (AFR)

AF:

0.476

AC:

19203

AN:

40342

American (AMR)

AF:

0.598

AC:

9051

AN:

15144

Ashkenazi Jewish (ASJ)

AF:

0.641

AC:

2210

AN:

3450

East Asian (EAS)

AF:

0.799

AC:

3923

AN:

4912

South Asian (SAS)

AF:

0.652

AC:

3028

AN:

4644

European-Finnish (FIN)

AF:

0.599

AC:

6252

AN:

10430

Middle Eastern (MID)

AF:

0.627

AC:

183

AN:

292

European-Non Finnish (NFE)

AF:

0.554

AC:

37346

AN:

67384

Other (OTH)

AF:

0.578

AC:

1195

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1599

3197

4796

6394

7993

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

716

1432

2148

2864

3580

<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:

0.556

Hom.:

10355

Bravo

AF:

0.553

EpiCase

AF:

0.562

EpiControl

AF:

0.569

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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.Arg374Arg in exon 6 of CYP11B2: This variant is not expected to have clinical significance because it has been identified in 80.16% (6876/8578) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs4538). -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

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

BayesDel_noAF

Benign

-0.60

CADD

Benign

6.2

(source)

DANN

Benign

0.64

PhyloP100

1.0

Mutation Taster

=70/30

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.050

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