rs34570566

Variant names:

• chr8-142876322-C-T
• rs34570566
• NM_000497.4:c.873G>A

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.873G>A​(p.Ala291Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0413 in 1,612,086 control chromosomes in the GnomAD database, including 3,002 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.086 (1078 hom., cov: 33)
  • Exomes 𝑓: 0.037 (1924 hom.)
• Consequence: CYP11B1 NM_000497.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.62
• Publications: 9 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=-0.81).
• BP6: Variant 8-142876322-C-T is Benign according to our data. Variant chr8-142876322-C-T is described in ClinVar as Benign. ClinVar VariationId is 362157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.62 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.217 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.873G>A	p.Ala291Ala	synonymous	Exon 5 of 9	NP_000488.3
	CYP11B1	NM_001026213.1		c.873G>A	p.Ala291Ala	synonymous	Exon 5 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.873G>A	p.Ala291Ala	synonymous	Exon 5 of 9	ENSP00000292427.5	P15538-1
	CYP11B1	ENST00000377675.3	TSL:1	c.1086G>A	p.Ala362Ala	synonymous	Exon 7 of 11	ENSP00000366903.3	Q4VAR0
	CYP11B1	ENST00000517471.5	TSL:1	c.873G>A	p.Ala291Ala	synonymous	Exon 5 of 8	ENSP00000428043.1	P15538-2

Frequencies

GnomAD3 genomes AF: 0.0855 AC: 12894 AN: 150874 Hom.: 1073 Cov.: 33

Gnomad AFR AF: 0.221

Gnomad AMI AF: 0.00989

Gnomad AMR AF: 0.0455

Gnomad ASJ AF: 0.0406

Gnomad EAS AF: 0.0788

Gnomad SAS AF: 0.0798

Gnomad FIN AF: 0.0376

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0258

Gnomad OTH AF: 0.0876

GnomAD2 exomes AF: 0.0536 AC: 13452 AN: 251052 AF XY: 0.0514

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.0418

Gnomad ASJ exome AF: 0.0492

Gnomad EAS exome AF: 0.0775

Gnomad FIN exome AF: 0.0400

Gnomad NFE exome AF: 0.0274

Gnomad OTH exome AF: 0.0453

GnomAD4 exome AF: 0.0368 AC: 53701 AN: 1461108 Hom.: 1924 Cov.: 34 AF XY: 0.0375 AC XY: 27266 AN XY: 726902

African (AFR) AF: 0.226 AC: 7440 AN: 32948

American (AMR) AF: 0.0424 AC: 1893 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.0516 AC: 1348 AN: 26134

East Asian (EAS) AF: 0.0692 AC: 2747 AN: 39698

South Asian (SAS) AF: 0.0735 AC: 6343 AN: 86252

European-Finnish (FIN) AF: 0.0383 AC: 2044 AN: 53418

Middle Eastern (MID) AF: 0.0963 AC: 555 AN: 5762

European-Non Finnish (NFE) AF: 0.0254 AC: 28290 AN: 1111942

Other (OTH) AF: 0.0504 AC: 3041 AN: 60302

GnomAD4 genome AF: 0.0855 AC: 12916 AN: 150978 Hom.: 1078 Cov.: 33 AF XY: 0.0851 AC XY: 6279 AN XY: 73824

African (AFR) AF: 0.221 AC: 8918 AN: 40312

American (AMR) AF: 0.0455 AC: 693 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.0406 AC: 141 AN: 3470

East Asian (EAS) AF: 0.0790 AC: 409 AN: 5180

South Asian (SAS) AF: 0.0803 AC: 387 AN: 4822

European-Finnish (FIN) AF: 0.0376 AC: 399 AN: 10618

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0258 AC: 1754 AN: 68018

Other (OTH) AF: 0.0863 AC: 182 AN: 2110

Alfa AF: 0.0638 Hom.: 311

Bravo AF: 0.0936

Asia WGS AF: 0.0920 AC: 317 AN: 3476

EpiCase AF: 0.0315

EpiControl AF: 0.0302

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.091
DANN	Benign	0.78
PhyloP100		-3.6
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: rs34570566; hg19: chr8-143957738; COSMIC: COSV52831284; COSMIC: COSV52831284;