8-142875024-C-T

Position:

chr8-142875024-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM5PP3_StrongPP5_Very_Strong

The ENST00000292427.10(CYP11B1):c.1331G>A(p.Gly444Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,614,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G444C) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

CYP11B1
ENST00000292427.10 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 4.98

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 Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in ENST00000292427.10

PM5

Other missense variant is known to change same aminoacid residue: Variant chr8-142875025-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2779333.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 8-142875024-C-T is Pathogenic according to our data. Variant chr8-142875024-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 235678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11B1	NM_000497.4 linkuse as main transcript	c.1331G>A	p.Gly444Asp	missense_variant	8/9	ENST00000292427.10	NP_000488.3
CYP11B1	NM_001026213.1 linkuse as main transcript	c.1200+210G>A		intron_variant			NP_001021384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP11B1	ENST00000292427.10 linkuse as main transcript	c.1331G>A	p.Gly444Asp	missense_variant	8/9	1	NM_000497.4	ENSP00000292427	P1	P15538-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251468

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135918

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.000478

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 13, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 23, 2022	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects CYP11B1 function (PMID: 15751602, 26053152). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CYP11B1 protein function. ClinVar contains an entry for this variant (Variation ID: 235678). This missense change has been observed in individual(s) with adrenal hyperplasia (PMID: 15751602, 26053152, 33275286). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine, which is neutral and non-polar, with aspartic acid, which is acidic and polar, at codon 444 of the CYP11B1 protein (p.Gly444Asp). -

Deficiency of steroid 11-beta-monooxygenase

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 24, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jan 16, 2018	- -

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

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 18, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.96

BayesDel_addAF

Pathogenic

0.45

BayesDel_noAF

Pathogenic

0.41

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T;D;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.87

D;T;T

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

3.2

.;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-6.5

D;D;D

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0040

D;D;D

Polyphen

1.0

.;D;D

Vest4

0.91, 0.98

MutPred

0.98

.;.;Loss of MoRF binding (P = 0.077);

MVP

0.95

MPC

0.52

ClinPred

1.0

GERP RS

4.2

Varity_R

0.99

gMVP

0.97

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