chr8-142875735-A-C

Variant names:

Variant summary

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

The NM_000497.4(CYP11B1):c.1098T>G(p.Arg366Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00482 in 1,599,246 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 53 hom., cov: 31)

Exomes 𝑓: 0.0035 ( 55 hom. )

Consequence

CYP11B1
NM_000497.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.00200

Publications

4 publications found

Variant links:

Genes affected

CYP11B1 (HGNC:2591): (cytochrome P450 family 11 subfamily B member 1) 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 and is involved in the conversion of progesterone to cortisol in the adrenal cortex. Mutations in this gene cause congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. Transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jul 2008]

CYP11B1 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=-0.67).

BP6

Variant 8-142875735-A-C is Benign according to our data. Variant chr8-142875735-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 362150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.002 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11B1	NM_000497.4 link	c.1098T>G	p.Arg366Arg	synonymous_variant	Exon 6 of 9	ENST00000292427.10	NP_000488.3	P15538-1Q8TDD0
CYP11B1	NM_001026213.1 link	c.1098T>G	p.Arg366Arg	synonymous_variant	Exon 6 of 8		NP_001021384.1	P15538-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP11B1	ENST00000292427.10 link	c.1098T>G	p.Arg366Arg	synonymous_variant	Exon 6 of 9	1	NM_000497.4	ENSP00000292427.5		P15538-1

Frequencies

GnomAD3 genomes

AF:

0.0192

AC:

2662

AN:

138716

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0589

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0107

Gnomad ASJ

AF:

0.00459

Gnomad EAS

AF:

0.00693

Gnomad SAS

AF:

0.0121

Gnomad FIN

AF:

0.00315

Gnomad MID

AF:

0.0317

Gnomad NFE

AF:

0.00371

Gnomad OTH

AF:

0.0151

GnomAD2 exomes

AF:

0.00608

AC:

1519

AN:

249754

AF XY:

0.00537

show subpopulations

Gnomad AFR exome

AF:

0.0467

Gnomad AMR exome

AF:

0.00506

Gnomad ASJ exome

AF:

0.00229

Gnomad EAS exome

AF:

0.00262

Gnomad FIN exome

AF:

0.000278

Gnomad NFE exome

AF:

0.00252

Gnomad OTH exome

AF:

0.00359

GnomAD4 exome

AF:

0.00346

AC:

5050

AN:

1460442

Hom.:

Cov.:

AF XY:

0.00345

AC XY:

2510

AN XY:

726556

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0445

AC:

1479

AN:

33238

American (AMR)

AF:

0.00472

AC:

211

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00203

AC:

AN:

26096

East Asian (EAS)

AF:

0.00470

AC:

186

AN:

39538

South Asian (SAS)

AF:

0.00637

AC:

549

AN:

86208

European-Finnish (FIN)

AF:

0.000338

AC:

AN:

53332

Middle Eastern (MID)

AF:

0.00643

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00199

AC:

2210

AN:

1111272

Other (OTH)

AF:

0.00509

AC:

307

AN:

60324

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.380

Heterozygous variant carriers

189

377

566

754

943

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

108

216

324

432

540

<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:

0.0192

AC:

2666

AN:

138804

Hom.:

Cov.:

AF XY:

0.0191

AC XY:

1294

AN XY:

67696

show subpopulations

African (AFR)

AF:

0.0588

AC:

2115

AN:

35948

American (AMR)

AF:

0.0107

AC:

149

AN:

13936

Ashkenazi Jewish (ASJ)

AF:

0.00459

AC:

AN:

3268

East Asian (EAS)

AF:

0.00695

AC:

AN:

4318

South Asian (SAS)

AF:

0.0120

AC:

AN:

4234

European-Finnish (FIN)

AF:

0.00315

AC:

AN:

9830

Middle Eastern (MID)

AF:

0.0303

AC:

AN:

264

European-Non Finnish (NFE)

AF:

0.00371

AC:

238

AN:

64172

Other (OTH)

AF:

0.0149

AC:

AN:

1942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

111

222

334

445

556

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.00960

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Dec 05, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Deficiency of steroid 11-beta-monooxygenase;C3838731:Glucocorticoid-remediable aldosteronism

Benign:1

May 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deficiency of steroid 11-beta-monooxygenase

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Glucocorticoid-remediable aldosteronism

Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.5

(source)

DANN

Benign

0.65

PhyloP100

-0.0020

PromoterAI

-0.021

Neutral

(source)

Mutation Taster

=99/1

polymorphism

(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