rs4546

Positions:

• chr8-142915137-G-A
• chr8-142915137-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000498.3(CYP11B2):​c.504C>T​(p.Phe168=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 1,612,206 control chromosomes in the GnomAD database, including 157,026 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12172 hom., cov: 31)
  • Exomes 𝑓: 0.44 (144854 hom.)
• Consequence: CYP11B2 NM_000498.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.58

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 8-142915137-G-A is Benign according to our data. Variant chr8-142915137-G-A is described in ClinVar as [Benign]. Clinvar id is 362221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-142915137-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.58 with no splicing effect.
• 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	UniProt
CYP11B2	NM_000498.3	c.504C>T	p.Phe168=	synonymous_variant	3/9	ENST00000323110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP11B2	ENST00000323110.2	c.504C>T	p.Phe168=	synonymous_variant	3/9	1	NM_000498.3	P1
GML	ENST00000522728.5	c.264+1092G>A		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58465 AN: 151792 Hom.: 12166 Cov.: 31

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.418

GnomAD3 exomes AF: 0.424 AC: 105583 AN: 248894 Hom.: 22865 AF XY: 0.431 AC XY: 58038 AN XY: 134608

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.292

Gnomad SAS exome AF: 0.428

Gnomad FIN exome AF: 0.494

Gnomad NFE exome AF: 0.446

Gnomad OTH exome AF: 0.442

GnomAD4 exome AF: 0.443 AC: 646392 AN: 1460298 Hom.: 144854 Cov.: 49 AF XY: 0.443 AC XY: 322145 AN XY: 726432

Gnomad4 AFR exome AF: 0.221

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: 0.385 AC: 58497 AN: 151908 Hom.: 12172 Cov.: 31 AF XY: 0.390 AC XY: 28956 AN XY: 74218

Gnomad4 AFR AF: 0.226

Gnomad4 AMR AF: 0.429

Gnomad4 ASJ AF: 0.541

Gnomad4 EAS AF: 0.297

Gnomad4 SAS AF: 0.419

Gnomad4 FIN AF: 0.479

Gnomad4 NFE AF: 0.451

Gnomad4 OTH AF: 0.415

Alfa AF: 0.427 Hom.: 5859

Bravo AF: 0.375

Asia WGS AF: 0.314 AC: 1093 AN: 3476

EpiCase AF: 0.459

EpiControl AF: 0.459

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Phe168Phe in exon 3 of CYP11B2: This variant is not expected to have clinical significance because it does not alter an amino acid residue, is not located wit hin the splice consensus sequence, and has been identified in 49.56% (3052/6158) of Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.b roadinstitute.org; dbSNP rs4546). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Corticosterone methyloxidase type 2 deficiency Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

Corticosterone 18-monooxygenase deficiency Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 02, 2021	- -

Corticosterone methyl oxidase type II deficiency Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

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
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.8
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4546; hg19: chr8-143996553; COSMIC: COSV59994442;