rs61752766

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_000497.4(CYP11B1):c.1003A>G(p.Asn335Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00046 in 1,613,276 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N335S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

CYP11B1
NM_000497.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: -1.54

Publications

2 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 -10 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000497.4

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: -1.5619 (below the threshold of 3.09). Trascript score misZ: -0.26962 (below the threshold of 3.09). GenCC associations: The gene is linked to glucocorticoid-remediable aldosteronism, congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency.

BP4

Computational evidence support a benign effect (MetaRNN=0.012870431).

BP6

Variant 8-142875830-T-C is Benign according to our data. Variant chr8-142875830-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35977.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00229 (348/151932) while in subpopulation AFR AF = 0.00765 (316/41328). AF 95% confidence interval is 0.00695. There are 2 homozygotes in GnomAd4. There are 167 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11B1	NM_000497.4 link	c.1003A>G	p.Asn335Asp	missense_variant	Exon 6 of 9	ENST00000292427.10	NP_000488.3	P15538-1Q8TDD0
CYP11B1	NM_001026213.1 link	c.1003A>G	p.Asn335Asp	missense_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.1003A>G	p.Asn335Asp	missense_variant	Exon 6 of 9	1	NM_000497.4	ENSP00000292427.5		P15538-1

Frequencies

GnomAD3 genomes

AF:

0.00229

AC:

347

AN:

151816

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00764

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000208

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000681

AC:

171

AN:

250920

AF XY:

0.000516

show subpopulations

Gnomad AFR exome

AF:

0.00827

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000881

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000270

AC:

394

AN:

1461344

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

171

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.00803

AC:

266

AN:

33122

American (AMR)

AF:

0.000403

AC:

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.000101

AC:

AN:

39700

South Asian (SAS)

AF:

0.000220

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000495

AC:

AN:

1111906

Other (OTH)

AF:

0.000514

AC:

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

103

129

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.00229

AC:

348

AN:

151932

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

167

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00765

AC:

316

AN:

41328

American (AMR)

AF:

0.00164

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.000194

AC:

AN:

5150

South Asian (SAS)

AF:

0.000208

AC:

AN:

4810

European-Finnish (FIN)

AF:

0.000189

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67970

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.164

Hom.:

6559

Bravo

AF:

0.00261

ESP6500AA

AF:

0.00749

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00124

AC:

151

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 23, 2016

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deficiency of steroid 11-beta-monooxygenase

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Congenital adrenal hyperplasia

Uncertain:1

Aug 18, 2011

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing;curation

- -

not provided

Benign:1

Nov 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

AlphaMissense

Benign

0.048

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.0080

(source)

DANN

Benign

0.47

DEOGEN2

Benign

0.10

T;.;.

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.0036

T;T;T

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.7

N;N;.

PhyloP100

-1.5

PrimateAI

Uncertain

0.63

PROVEAN

Benign

1.4

N;N;N

REVEL

Benign

0.017

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.093

MVP

0.48

MPC

0.096

ClinPred

0.0014

GERP RS

-0.98

PromoterAI

0.012

Neutral

(source)

Varity_R

0.11

gMVP

0.65

Mutation Taster

=96/4

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