rs4539

Positions:

• chr8-142915123-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000498.3(CYP11B2):​c.518A>G​(p.Lys173Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 151,876 control chromosomes in the GnomAD database, including 12,203 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12203 hom., cov: 31)
  • Exomes 𝑓: 0.44 (144826 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP11B2 NM_000498.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.530

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]

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=3.9825718E-5).
• BP6: Variant 8-142915123-T-C is Benign according to our data. Variant chr8-142915123-T-C is described in ClinVar as [Benign]. Clinvar id is 362220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-142915123-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11B2	NM_000498.3	c.518A>G	p.Lys173Arg	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	c.518A>G	p.Lys173Arg	missense_variant	3/9	1	NM_000498.3	ENSP00000325822	P1
GML	ENST00000522728.5	c.264+1078T>C		intron_variant		3		ENSP00000430799

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58596 AN: 151760 Hom.: 12195 Cov.: 31

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.420

GnomAD3 exomes AF: 0.424 AC: 105290 AN: 248332 Hom.: 22722 AF XY: 0.431 AC XY: 57848 AN XY: 134284

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.291

Gnomad SAS exome AF: 0.428

Gnomad FIN exome AF: 0.493

Gnomad NFE exome AF: 0.446

Gnomad OTH exome AF: 0.443

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.443 AC: 646367 AN: 1459998 Hom.: 144826 Cov.: 47 AF XY: 0.444 AC XY: 322074 AN XY: 726180

Gnomad4 AFR exome AF: 0.224

Gnomad4 AMR exome AF: 0.431

Gnomad4 ASJ exome AF: 0.549

Gnomad4 EAS exome AF: 0.318

Gnomad4 SAS exome AF: 0.432

Gnomad4 FIN exome AF: 0.498

Gnomad4 NFE exome AF: 0.450

Gnomad4 OTH exome AF: 0.443

GnomAD4 genome AF: 0.386 AC: 58630 AN: 151876 Hom.: 12203 Cov.: 31 AF XY: 0.391 AC XY: 29016 AN XY: 74202

Gnomad4 AFR AF: 0.229

Gnomad4 AMR AF: 0.430

Gnomad4 ASJ AF: 0.541

Gnomad4 EAS AF: 0.297

Gnomad4 SAS AF: 0.420

Gnomad4 FIN AF: 0.480

Gnomad4 NFE AF: 0.451

Gnomad4 OTH AF: 0.417

Alfa AF: 0.428 Hom.: 6085

Bravo AF: 0.376

ESP6500AA AF: 0.236 AC: 1038

ESP6500EA AF: 0.449 AC: 3857

ExAC AF: 0.417 AC: 50583

EpiCase AF: 0.459

EpiControl AF: 0.459

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Lys173Arg in exon 3 of CYP11B2: This variant is not expected to have clinical significance because it has been identified in 49.39% (2973/6020) of Finnish chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs4539). -

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 21, 2018	This variant is associated with the following publications: (PMID: 8954040) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Corticosterone methyloxidase type 2 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Corticosterone 18-monooxygenase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Corticosterone methyl oxidase type II deficiency Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 23, 2019

- -

Corticosterone 18-monooxygenase deficiency;C3463917:Corticosterone methyloxidase type 2 deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 29, 2021

- -

Glucocorticoid-remediable aldosteronism Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.20
DANN	Benign	0.36
DEOGEN2	Benign	0.092	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.000040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.33	N
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.035
Sift	Benign	0.62	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.052
MPC		0.20
ClinPred		0.0081	T
GERP RS		-4.2
Varity_R		0.10
gMVP		0.64

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

Other links and lift over

dbSNP: rs4539; hg19: chr8-143996539; COSMIC: COSV59995600;