chr8-142913286-G-T

Position:

• chr8-142913286-G-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.1120C>A​(p.Arg374Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.569 in 1,610,144 control chromosomes in the GnomAD database, including 263,098 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.55 (23124 hom., cov: 29)
  • Exomes 𝑓: 0.57 (239974 hom.)
• Consequence: CYP11B2 NM_000498.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001083
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.01

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=-0.6).
• BP6: Variant 8-142913286-G-T is Benign according to our data. Variant chr8-142913286-G-T is described in ClinVar as [Benign]. Clinvar id is 362195.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-142913286-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.01 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.778 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11B2	NM_000498.3	c.1120C>A	p.Arg374Arg	splice_region_variant, synonymous_variant	6/9	ENST00000323110.2	NP_000489.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP11B2	ENST00000323110.2	c.1120C>A	p.Arg374Arg	splice_region_variant, synonymous_variant	6/9	1	NM_000498.3	ENSP00000325822.2
GML	ENST00000522728.5	c.182-677G>T		intron_variant		3		ENSP00000430799.1

Frequencies

GnomAD3 genomes AF: 0.554 AC: 82848 AN: 149446 Hom.: 23113 Cov.: 29

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.597

Gnomad ASJ AF: 0.641

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.554

Gnomad OTH AF: 0.581

GnomAD3 exomes AF: 0.600 AC: 148144 AN: 247034 Hom.: 45016 AF XY: 0.603 AC XY: 80953 AN XY: 134174

Gnomad AFR exome AF: 0.488

Gnomad AMR exome AF: 0.608

Gnomad ASJ exome AF: 0.643

Gnomad EAS exome AF: 0.805

Gnomad SAS exome AF: 0.656

Gnomad FIN exome AF: 0.620

Gnomad NFE exome AF: 0.556

Gnomad OTH exome AF: 0.588

GnomAD4 exome AF: 0.571 AC: 833445 AN: 1460576 Hom.: 239974 Cov.: 62 AF XY: 0.574 AC XY: 417045 AN XY: 726610

Gnomad4 AFR exome AF: 0.484

Gnomad4 AMR exome AF: 0.604

Gnomad4 ASJ exome AF: 0.645

Gnomad4 EAS exome AF: 0.808

Gnomad4 SAS exome AF: 0.664

Gnomad4 FIN exome AF: 0.616

Gnomad4 NFE exome AF: 0.551

Gnomad4 OTH exome AF: 0.585

GnomAD4 genome AF: 0.554 AC: 82890 AN: 149568 Hom.: 23124 Cov.: 29 AF XY: 0.562 AC XY: 41032 AN XY: 72974

Gnomad4 AFR AF: 0.476

Gnomad4 AMR AF: 0.598

Gnomad4 ASJ AF: 0.641

Gnomad4 EAS AF: 0.799

Gnomad4 SAS AF: 0.652

Gnomad4 FIN AF: 0.599

Gnomad4 NFE AF: 0.554

Gnomad4 OTH AF: 0.578

Alfa AF: 0.539 Hom.: 6041

Bravo AF: 0.553

EpiCase AF: 0.562

EpiControl AF: 0.569

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2016	p.Arg374Arg in exon 6 of CYP11B2: This variant is not expected to have clinical significance because it has been identified in 80.16% (6876/8578) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs4538). -
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, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Corticosterone methyloxidase type 2 deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 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	Mar 06, 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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Mar 06, 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	-0.60
CADD	Benign	6.2
DANN	Benign	0.64

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00011
dbscSNV1_RF	Benign	0.050
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: rs4538; hg19: chr8-143994702; COSMIC: COSV59996516;