8-142874500-C-G

Variant names:

• chr8-142874500-C-G
• rs5295
• NM_000497.4:c.1399-14G>C

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.1399-14G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0874 in 1,587,936 control chromosomes in the GnomAD database, including 7,518 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1575 hom., cov: 32)
  • Exomes 𝑓: 0.084 (5943 hom.)
• Consequence: CYP11B1 NM_000497.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -2.56

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=-0.84).
• BP6: Variant 8-142874500-C-G is Benign according to our data. Variant chr8-142874500-C-G is described in ClinVar as [Benign]. Clinvar id is 362146.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-142874500-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.235 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYP11B1	NM_000497.4	c.1399-14G>C		intron_variant	Intron 8 of 8	ENST00000292427.10	NP_000488.3
CYP11B1	NM_001026213.1	c.1201-14G>C		intron_variant	Intron 7 of 7		NP_001021384.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYP11B1	ENST00000292427.10	c.1399-14G>C		intron_variant	Intron 8 of 8	1	NM_000497.4	ENSP00000292427.5

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18555 AN: 151956 Hom.: 1569 Cov.: 32

Gnomad AFR AF: 0.239

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.0706

Gnomad ASJ AF: 0.0616

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0925

Gnomad FIN AF: 0.0735

Gnomad MID AF: 0.189

Gnomad NFE AF: 0.0853

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.0844 AC: 21172 AN: 250882 Hom.: 1226 AF XY: 0.0842 AC XY: 11419 AN XY: 135626

Gnomad AFR exome AF: 0.243

Gnomad AMR exome AF: 0.0489

Gnomad ASJ exome AF: 0.0581

Gnomad EAS exome AF: 0.000381

Gnomad SAS exome AF: 0.0959

Gnomad FIN exome AF: 0.0718

Gnomad NFE exome AF: 0.0879

Gnomad OTH exome AF: 0.0819

GnomAD4 exome AF: 0.0837 AC: 120201 AN: 1435862 Hom.: 5943 Cov.: 26 AF XY: 0.0841 AC XY: 60236 AN XY: 715964

Gnomad4 AFR exome AF: 0.247

Gnomad4 AMR exome AF: 0.0525

Gnomad4 ASJ exome AF: 0.0601

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.101

Gnomad4 FIN exome AF: 0.0688

Gnomad4 NFE exome AF: 0.0828

Gnomad4 OTH exome AF: 0.0816

GnomAD4 genome AF: 0.122 AC: 18582 AN: 152074 Hom.: 1575 Cov.: 32 AF XY: 0.119 AC XY: 8859 AN XY: 74346

Gnomad4 AFR AF: 0.239

Gnomad4 AMR AF: 0.0704

Gnomad4 ASJ AF: 0.0616

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.0932

Gnomad4 FIN AF: 0.0735

Gnomad4 NFE AF: 0.0854

Gnomad4 OTH AF: 0.110

Alfa AF: 0.0624 Hom.: 89

Bravo AF: 0.126

Asia WGS AF: 0.0480 AC: 170 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Deficiency of steroid 11-beta-monooxygenase Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 20, 2020

Department of Human Genetics, Laborarztpraxis Dres. Walther, Weindel und Kollegen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Aug 02, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glucocorticoid-remediable aldosteronism Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.84
CADD	Benign	0.17
DANN	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs5295; hg19: chr8-143955916; COSMIC: COSV52827254;