8-142914345-C-T

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.873G>A(p.Ala291=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.952 in 1,613,702 control chromosomes in the GnomAD database, including 737,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67590 hom., cov: 32)
  • Exomes 𝑓: 0.95 (670311 hom.)
• Consequence: CYP11B2 NM_000498.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -5.37

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=-0.96).
• BP6: Variant 8-142914345-C-T is Benign according to our data. Variant chr8-142914345-C-T is described in ClinVar as [Benign]. Clinvar id is 362207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-142914345-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-5.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.974 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP11B2	NM_000498.3	c.873G>A	p.Ala291=	synonymous_variant	5/9	ENST00000323110.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP11B2	ENST00000323110.2	c.873G>A	p.Ala291=	synonymous_variant	5/9	1	NM_000498.3	P1
GML	ENST00000522728.5	c.264+300C>T		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.938 AC: 142591 AN: 152082 Hom.: 67546 Cov.: 32

Gnomad AFR AF: 0.947

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.889

Gnomad ASJ AF: 0.963

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.950

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.980

Gnomad OTH AF: 0.935

GnomAD3 exomes AF: 0.905 AC: 227291 AN: 251258 Hom.: 105014 AF XY: 0.908 AC XY: 123328 AN XY: 135818

Gnomad AFR exome AF: 0.946

Gnomad AMR exome AF: 0.858

Gnomad ASJ exome AF: 0.967

Gnomad EAS exome AF: 0.477

Gnomad SAS exome AF: 0.853

Gnomad FIN exome AF: 0.947

Gnomad NFE exome AF: 0.981

Gnomad OTH exome AF: 0.935

GnomAD4 exome AF: 0.954 AC: 1393549 AN: 1461502 Hom.: 670311 Cov.: 41 AF XY: 0.951 AC XY: 691593 AN XY: 727074

Gnomad4 AFR exome AF: 0.951

Gnomad4 AMR exome AF: 0.864

Gnomad4 ASJ exome AF: 0.968

Gnomad4 EAS exome AF: 0.487

Gnomad4 SAS exome AF: 0.855

Gnomad4 FIN exome AF: 0.949

Gnomad4 NFE exome AF: 0.982

Gnomad4 OTH exome AF: 0.936

GnomAD4 genome AF: 0.938 AC: 142691 AN: 152200 Hom.: 67590 Cov.: 32 AF XY: 0.931 AC XY: 69225 AN XY: 74390

Gnomad4 AFR AF: 0.947

Gnomad4 AMR AF: 0.889

Gnomad4 ASJ AF: 0.963

Gnomad4 EAS AF: 0.481

Gnomad4 SAS AF: 0.839

Gnomad4 FIN AF: 0.950

Gnomad4 NFE AF: 0.980

Gnomad4 OTH AF: 0.934

Alfa AF: 0.971 Hom.: 30980

Bravo AF: 0.935

Asia WGS AF: 0.699 AC: 2435 AN: 3478

EpiCase AF: 0.985

EpiControl AF: 0.984

ClinVar

Significance: Benign

Submissions summary: Benign:11

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, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Ala291Ala in exon 5 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 97.79% (65226/6669 8) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exa c.broadinstitute.org; dbSNP rs4536). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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	Jan 12, 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. -

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	Jan 12, 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. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 18, 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 12, 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	-0.96
Cadd	Benign	0.023
Dann	Benign	0.63

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: rs4536; hg19: chr8-143995761; COSMIC: COSV59998409;