rs61752766

Positions:

chr8-142875830-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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 made for transcript

Verdict is Benign. Variant got -13 ACMG points.

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 id is 35977.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=3}.

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11B1	NM_000497.4 linkuse as main transcript	c.1003A>G	p.Asn335Asp	missense_variant	6/9	ENST00000292427.10	NP_000488.3
CYP11B1	NM_001026213.1 linkuse as main transcript	c.1003A>G	p.Asn335Asp	missense_variant	6/8		NP_001021384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP11B1	ENST00000292427.10 linkuse as main transcript	c.1003A>G	p.Asn335Asp	missense_variant	6/9	1	NM_000497.4	ENSP00000292427	P1	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

GnomAD3 exomes

AF:

0.000681

AC:

171

AN:

250920

Hom.:

AF XY:

0.000516

AC XY:

AN XY:

135724

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 SAS exome

AF:

0.000196

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

Gnomad4 AFR exome

AF:

0.00803

Gnomad4 AMR exome

AF:

0.000403

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000220

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000495

Gnomad4 OTH exome

AF:

0.000514

GnomAD4 genome

AF:

0.00229

AC:

348

AN:

151932

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

167

AN XY:

74314

show subpopulations

Gnomad4 AFR

AF:

0.00765

Gnomad4 AMR

AF:

0.00164

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000208

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00104

Hom.:

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

Uncertain significance, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 23, 2016

- -

Deficiency of steroid 11-beta-monooxygenase

Uncertain:1

Uncertain significance, 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, 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

Uncertain significance, criteria provided, single submitter

clinical testing;curation

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

Aug 18, 2011

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 30, 2024

- -

Glucocorticoid-remediable aldosteronism

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. -

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

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;.

MutationTaster

Benign

1.0

N;N;N

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

Varity_R

0.11

gMVP

0.65

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