8-142879589-T-C

Variant names:

• chr8-142879589-T-C
• rs6410
• NM_000497.4:c.225A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000497.4(CYP11B1):​c.225A>G​(p.Leu75Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 1,613,808 control chromosomes in the GnomAD database, including 248,147 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (22062 hom., cov: 33)
  • Exomes 𝑓: 0.55 (226085 hom.)
• Consequence: CYP11B1 NM_000497.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.644
• Publications: 32 publications found

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 8-142879589-T-C is Benign according to our data. Variant chr8-142879589-T-C is described in ClinVar as Benign. ClinVar VariationId is 362169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.644 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.743 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000497.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	NM_000497.4	MANE Select	c.225A>G	p.Leu75Leu	synonymous	Exon 1 of 9	NP_000488.3
	CYP11B1	NM_001026213.1		c.225A>G	p.Leu75Leu	synonymous	Exon 1 of 8	NP_001021384.1	P15538-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	ENST00000292427.10	TSL:1 MANE Select	c.225A>G	p.Leu75Leu	synonymous	Exon 1 of 9	ENSP00000292427.5	P15538-1
	CYP11B1	ENST00000377675.3	TSL:1	c.225A>G	p.Leu75Leu	synonymous	Exon 1 of 11	ENSP00000366903.3	Q4VAR0
	CYP11B1	ENST00000517471.5	TSL:1	c.225A>G	p.Leu75Leu	synonymous	Exon 1 of 8	ENSP00000428043.1	P15538-2

Frequencies

GnomAD3 genomes AF: 0.534 AC: 81132 AN: 151938 Hom.: 22054 Cov.: 33

Gnomad AFR AF: 0.440

Gnomad AMI AF: 0.548

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.580

Gnomad EAS AF: 0.764

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.578

Gnomad MID AF: 0.589

Gnomad NFE AF: 0.542

Gnomad OTH AF: 0.541

GnomAD2 exomes AF: 0.581 AC: 145878 AN: 251126 AF XY: 0.585

Gnomad AFR exome AF: 0.437

Gnomad AMR exome AF: 0.615

Gnomad ASJ exome AF: 0.571

Gnomad EAS exome AF: 0.759

Gnomad FIN exome AF: 0.590

Gnomad NFE exome AF: 0.541

Gnomad OTH exome AF: 0.568

GnomAD4 exome AF: 0.553 AC: 808246 AN: 1461756 Hom.: 226085 Cov.: 68 AF XY: 0.557 AC XY: 404750 AN XY: 727186

African (AFR) AF: 0.433 AC: 14505 AN: 33480

American (AMR) AF: 0.610 AC: 27277 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 14864 AN: 26134

East Asian (EAS) AF: 0.769 AC: 30516 AN: 39698

South Asian (SAS) AF: 0.665 AC: 57397 AN: 86256

European-Finnish (FIN) AF: 0.588 AC: 31395 AN: 53390

Middle Eastern (MID) AF: 0.589 AC: 3397 AN: 5764

European-Non Finnish (NFE) AF: 0.535 AC: 595089 AN: 1111934

Other (OTH) AF: 0.560 AC: 33806 AN: 60388

GnomAD4 genome AF: 0.534 AC: 81172 AN: 152052 Hom.: 22062 Cov.: 33 AF XY: 0.542 AC XY: 40303 AN XY: 74318

African (AFR) AF: 0.440 AC: 18248 AN: 41488

American (AMR) AF: 0.592 AC: 9046 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.580 AC: 2011 AN: 3468

East Asian (EAS) AF: 0.763 AC: 3932 AN: 5154

South Asian (SAS) AF: 0.660 AC: 3182 AN: 4824

European-Finnish (FIN) AF: 0.578 AC: 6114 AN: 10580

Middle Eastern (MID) AF: 0.585 AC: 172 AN: 294

European-Non Finnish (NFE) AF: 0.542 AC: 36832 AN: 67938

Other (OTH) AF: 0.538 AC: 1136 AN: 2110

Alfa AF: 0.537 Hom.: 75034

Bravo AF: 0.526

Asia WGS AF: 0.639 AC: 2223 AN: 3478

EpiCase AF: 0.540

EpiControl AF: 0.550

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Deficiency of steroid 11-beta-monooxygenase (3)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Glucocorticoid-remediable aldosteronism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	9.1
DANN	Benign	0.84
PhyloP100		-0.64
PromoterAI		0.0042	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6410; hg19: chr8-143961005; COSMIC: COSV52829502; COSMIC: COSV52829502;