rs3097

Positions:

• chr8-142911899-C-T

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.*81G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 1,599,268 control chromosomes in the GnomAD database, including 59,115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3912 hom., cov: 31)
  • Exomes 𝑓: 0.27 (55203 hom.)
• Consequence: CYP11B2 NM_000498.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0500

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 (BayesDel_noAF=-0.8).
• BP6: Variant 8-142911899-C-T is Benign according to our data. Variant chr8-142911899-C-T is described in ClinVar as [Benign]. Clinvar id is 362191.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-142911899-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CYP11B2	NM_000498.3	c.*81G>A		3_prime_UTR_variant	9/9	ENST00000323110.2	NP_000489.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CYP11B2	ENST00000323110	c.*81G>A		3_prime_UTR_variant	9/9	1	NM_000498.3	ENSP00000325822.2
GML	ENST00000522728.5	c.182-2064C>T		intron_variant		3		ENSP00000430799.1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30343 AN: 151388 Hom.: 3917 Cov.: 31

Gnomad AFR AF: 0.0528

Gnomad AMI AF: 0.194

Gnomad AMR AF: 0.183

Gnomad ASJ AF: 0.246

Gnomad EAS AF: 0.0601

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.220

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.196

GnomAD4 exome AF: 0.269 AC: 389110 AN: 1447764 Hom.: 55203 Cov.: 30 AF XY: 0.267 AC XY: 192425 AN XY: 719620

Gnomad4 AFR exome AF: 0.0457

Gnomad4 AMR exome AF: 0.138

Gnomad4 ASJ exome AF: 0.246

Gnomad4 EAS exome AF: 0.0608

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.262

Gnomad4 NFE exome AF: 0.297

Gnomad4 OTH exome AF: 0.247

GnomAD4 genome AF: 0.200 AC: 30322 AN: 151504 Hom.: 3912 Cov.: 31 AF XY: 0.196 AC XY: 14477 AN XY: 74018

Gnomad4 AFR AF: 0.0526

Gnomad4 AMR AF: 0.182

Gnomad4 ASJ AF: 0.246

Gnomad4 EAS AF: 0.0605

Gnomad4 SAS AF: 0.186

Gnomad4 FIN AF: 0.265

Gnomad4 NFE AF: 0.293

Gnomad4 OTH AF: 0.193

Alfa AF: 0.236 Hom.: 572

Bravo AF: 0.188

Asia WGS AF: 0.134 AC: 465 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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 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. -

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:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

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	-0.80
CADD	Benign	4.5
DANN	Benign	0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3097; hg19: chr8-143993315; COSMIC: COSV59996750;