rs61752769

chr8-142875735-A-Cchr8-142875735-A-T

Variant summary

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

The NM_000497.4(CYP11B1):c.1098T>G(p.Arg366=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00482 in 1,599,246 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (53 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (55 hom.)
• Consequence: CYP11B1 NM_000497.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.00200

Genes affected

CYP11B1 (HGNC:2591): (cytochrome P450 family 11 subfamily B member 1) 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 and is involved in the conversion of progesterone to cortisol in the adrenal cortex. Mutations in this gene cause congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency. Transcript variants encoding different isoforms have been noted for this gene. [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=-0.67).
• BP6: Variant 8-142875735-A-C is Benign according to our data. Variant chr8-142875735-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 362150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.002 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0567 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP11B1	NM_000497.4	c.1098T>G	p.Arg366=	synonymous_variant	6/9	ENST00000292427.10
CYP11B1	NM_001026213.1	c.1098T>G	p.Arg366=	synonymous_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP11B1	ENST00000292427.10	c.1098T>G	p.Arg366=	synonymous_variant	6/9	1	NM_000497.4	P1

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2662 AN: 138716 Hom.: 53 Cov.: 31

Gnomad AFR AF: 0.0589

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0107

Gnomad ASJ AF: 0.00459

Gnomad EAS AF: 0.00693

Gnomad SAS AF: 0.0121

Gnomad FIN AF: 0.00315

Gnomad MID AF: 0.0317

Gnomad NFE AF: 0.00371

Gnomad OTH AF: 0.0151

GnomAD3 exomes AF: 0.00608 AC: 1519 AN: 249754 Hom.: 26 AF XY: 0.00537 AC XY: 726 AN XY: 135216

Gnomad AFR exome AF: 0.0467

Gnomad AMR exome AF: 0.00506

Gnomad ASJ exome AF: 0.00229

Gnomad EAS exome AF: 0.00262

Gnomad SAS exome AF: 0.00680

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00252

Gnomad OTH exome AF: 0.00359

GnomAD4 exome AF: 0.00346 AC: 5050 AN: 1460442 Hom.: 55 Cov.: 33 AF XY: 0.00345 AC XY: 2510 AN XY: 726556

Gnomad4 AFR exome AF: 0.0445

Gnomad4 AMR exome AF: 0.00472

Gnomad4 ASJ exome AF: 0.00203

Gnomad4 EAS exome AF: 0.00470

Gnomad4 SAS exome AF: 0.00637

Gnomad4 FIN exome AF: 0.000338

Gnomad4 NFE exome AF: 0.00199

Gnomad4 OTH exome AF: 0.00509

GnomAD4 genome AF: 0.0192 AC: 2666 AN: 138804 Hom.: 53 Cov.: 31 AF XY: 0.0191 AC XY: 1294 AN XY: 67696

Gnomad4 AFR AF: 0.0588

Gnomad4 AMR AF: 0.0107

Gnomad4 ASJ AF: 0.00459

Gnomad4 EAS AF: 0.00695

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.00315

Gnomad4 NFE AF: 0.00371

Gnomad4 OTH AF: 0.0149

Alfa AF: 0.00960 Hom.: 12

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 05, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Deficiency of steroid 11-beta-monooxygenase;C3838731:Glucocorticoid-remediable aldosteronism Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 11, 2022

- -

Deficiency of steroid 11-beta-monooxygenase Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

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	-0.67
Cadd	Benign	7.5
Dann	Benign	0.65

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: rs61752769; hg19: chr8-143957151; COSMIC: COSV52824756;