8-142877011-C-T

Position:

• chr8-142877011-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000497.4(CYP11B1):​c.595+12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.546 in 1,612,492 control chromosomes in the GnomAD database, including 244,449 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.51 (20741 hom., cov: 31)
  • Exomes 𝑓: 0.55 (223708 hom.)
• Consequence: CYP11B1 NM_000497.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.01

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-142877011-C-T is Benign according to our data. Variant chr8-142877011-C-T is described in ClinVar as [Benign]. Clinvar id is 362164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-142877011-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CYP11B1	NM_000497.4	c.595+12G>A		intron_variant		ENST00000292427.10
CYP11B1	NM_001026213.1	c.595+12G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CYP11B1	ENST00000292427.10	c.595+12G>A		intron_variant		1	NM_000497.4	P1

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77902 AN: 151806 Hom.: 20731 Cov.: 31

Gnomad AFR AF: 0.368

Gnomad AMI AF: 0.549

Gnomad AMR AF: 0.586

Gnomad ASJ AF: 0.607

Gnomad EAS AF: 0.768

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.575

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.540

Gnomad OTH AF: 0.529

GnomAD3 exomes AF: 0.576 AC: 143035 AN: 248318 Hom.: 42067 AF XY: 0.582 AC XY: 78194 AN XY: 134322

Gnomad AFR exome AF: 0.363

Gnomad AMR exome AF: 0.609

Gnomad ASJ exome AF: 0.597

Gnomad EAS exome AF: 0.764

Gnomad SAS exome AF: 0.657

Gnomad FIN exome AF: 0.588

Gnomad NFE exome AF: 0.540

Gnomad OTH exome AF: 0.564

GnomAD4 exome AF: 0.550 AC: 802989 AN: 1460568 Hom.: 223708 Cov.: 64 AF XY: 0.554 AC XY: 402324 AN XY: 726488

Gnomad4 AFR exome AF: 0.360

Gnomad4 AMR exome AF: 0.604

Gnomad4 ASJ exome AF: 0.596

Gnomad4 EAS exome AF: 0.771

Gnomad4 SAS exome AF: 0.664

Gnomad4 FIN exome AF: 0.586

Gnomad4 NFE exome AF: 0.533

Gnomad4 OTH exome AF: 0.557

GnomAD4 genome AF: 0.513 AC: 77941 AN: 151924 Hom.: 20741 Cov.: 31 AF XY: 0.522 AC XY: 38762 AN XY: 74248

Gnomad4 AFR AF: 0.368

Gnomad4 AMR AF: 0.586

Gnomad4 ASJ AF: 0.607

Gnomad4 EAS AF: 0.767

Gnomad4 SAS AF: 0.657

Gnomad4 FIN AF: 0.575

Gnomad4 NFE AF: 0.540

Gnomad4 OTH AF: 0.528

Alfa AF: 0.481 Hom.: 2685

Bravo AF: 0.503

Asia WGS AF: 0.638 AC: 2220 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of steroid 11-beta-monooxygenase Benign:3

Benign, criteria provided, single submitter	clinical testing	Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen	Apr 20, 2020	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -

not specified Benign:2

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+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 25, 2019	This variant is associated with the following publications: (PMID: 23291679) -

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	-0.90
CADD	Benign	1.4
DANN	Benign	0.91

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: rs6387; hg19: chr8-143958427;