rs28931609

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PP3_StrongPP5

The NM_000498.3(CYP11B2):c.541C>T(p.Arg181Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000297 in 1,613,704 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

CYP11B2
NM_000498.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3

Conservation

PhyloP100: 1.62

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 made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.992

PP5

Variant 8-142915100-G-A is Pathogenic according to our data. Variant chr8-142915100-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242773.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11B2	NM_000498.3 linkuse as main transcript	c.541C>T	p.Arg181Trp	missense_variant	3/9	ENST00000323110.2	NP_000489.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP11B2	ENST00000323110.2 linkuse as main transcript	c.541C>T	p.Arg181Trp	missense_variant	3/9	1	NM_000498.3	ENSP00000325822	P1
GML	ENST00000522728.5 linkuse as main transcript	c.264+1055G>A		intron_variant		3		ENSP00000430799

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152156

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000200

AC:

AN:

249592

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135042

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000290

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:

0.0000266

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1461548

Hom.:

Cov.:

AF XY:

0.0000275

AC XY:

AN XY:

727034

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152156

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74316

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2021	Observed in the homozygous state in individuals with aldosterone synthase deficiency in published literature, however these individuals were also homozygous for an additional variant in the CYP11B2 gene. Additionally, the R181W variant alone was observed in the homozygous state in several unaffected family members (Pascoe et al., 1992; Mitsuuchi et al., 1992); Observed with additional variant(s) in the CYP11B2 gene in patients with aldosterone synthase deficiency type II, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes in some cases (Zhang et al., 1995; Leshinsky-Silver et al., 2006); Published functional studies demonstrate a damaging effect with a defect in 18-oxidation (Pascoe et al., 1992; Tin et al., 2011); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 7792802, 1594605, 25102047, 7485152, 12788848, 1346492, 22801770, 33098647, 21237269, 16733366) -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 181 of the CYP11B2 protein (p.Arg181Trp). This variant is present in population databases (rs28931609, gnomAD 0.004%). This variant when in cis with p.Val386Ala has been observed in multiple individuals affected with hypoaldosteronism and reported to segregate with disease (PMID: 1594605, 7485152, 16733366, 1346492). The clinical significance of this variant independent of the p.Val386Ala variant is unclear and has only been reported in one individual (PMID: 16733366). ClinVar contains an entry for this variant (Variation ID: 242773). 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 not expected to disrupt CYP11B2 protein function with a negative predictive value of 95%. This variant has been reported to affect CYP11B2 protein function both on its own and when in cis with p.Val386Ala (PMID: 7792802, 12788848). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Early-onset familial hypoaldosteronism

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Clinical Biochemistry Laboratory, Health Services Laboratory

Aug 27, 2024

We observed this variant in 2 cases in our laboratory, both with the expected clinical and biochemical phenotype (hyperreninaemia, hyponatraemia) and urine steroid metabolites indicative of aldosterone synthase deficiency. One case was homozygous for c.541C>T (p.R181W) in cis with c.1157T>C (p.V386A). In the second case c.1157T>C was not present and the individual was a compound heterozygote with c.1471C>T (p.Pro491Ser), confirmed in trans by family studies. We applied codes PM2, PM3, PP3, and PP4. Our conclusion is supported by publications from Pascoe 1992 (PMID1594605) and Zhang 1995 (PMID 7485152) which both show p.R181W to have a significant loss of activity in vitro expressed in two different cell types. ACMG:PM2 PM3 PP3 PP4 -

Corticosterone methyl oxidase type II deficiency

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.0012

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.54

Eigen

Uncertain

0.21

Eigen_PC

Benign

0.0074

FATHMM_MKL

Benign

0.47

LIST_S2

Benign

0.73

M_CAP

Pathogenic

0.56

MetaRNN

Pathogenic

0.99

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.6

MutationTaster

Benign

1.3e-7

PrimateAI

Benign

0.39

PROVEAN

Pathogenic

-5.9

REVEL

Uncertain

0.43

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.012

Polyphen

0.99

Vest4

0.69

MutPred

0.79

Gain of catalytic residue at A180 (P = 0.0332);

MVP

0.85

MPC

0.83

ClinPred

0.86

GERP RS

3.4

Varity_R

0.67

gMVP

0.79

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