rs61752794

Variant names:

• chr8-142875332-T-C
• rs61752794
• ENST00000519285.5:c.136A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The ENST00000519285.5(CYP11B1):​c.136A>G​(p.Met46Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0106 in 1,575,564 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/16 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M46T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (18 hom., cov: 32)
  • Exomes 𝑓: 0.010 (88 hom.)
• Consequence: CYP11B1 ENST00000519285.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.86
• Publications: 4 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 -12 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 45 curated pathogenic missense variants (we use a threshold of 10). The gene has 9 curated benign missense variants. Gene score misZ: -1.5619 (below the threshold of 3.09). Trascript score misZ: 0.21772 (below the threshold of 3.09). GenCC associations: The gene is linked to glucocorticoid-remediable aldosteronism, congenital adrenal hyperplasia due to 11-beta-hydroxylase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0036462545).
• BP6: Variant 8-142875332-T-C is Benign according to our data. Variant chr8-142875332-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 35984.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0164 (2295/139844) while in subpopulation AFR AF = 0.0222 (893/40174). AF 95% confidence interval is 0.021. There are 18 homozygotes in GnomAd4. There are 1143 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 18 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000519285.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	NM_000497.4	MANE Select	c.1122-20A>G		intron	N/A	NP_000488.3
	CYP11B1	NM_001026213.1		c.1122-20A>G		intron	N/A	NP_001021384.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B1	ENST00000519285.5	TSL:1	c.136A>G	p.Met46Val	missense	Exon 2 of 4	ENSP00000430144.1
	CYP11B1	ENST00000292427.10	TSL:1 MANE Select	c.1122-20A>G		intron	N/A	ENSP00000292427.5
	CYP11B1	ENST00000377675.3	TSL:1	c.1335-20A>G		intron	N/A	ENSP00000366903.3

Frequencies

GnomAD3 genomes AF: 0.0165 AC: 2299 AN: 139734 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0223

Gnomad AMI AF: 0.0138

Gnomad AMR AF: 0.00830

Gnomad ASJ AF: 0.0180

Gnomad EAS AF: 0.00668

Gnomad SAS AF: 0.0148

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.0142

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.00938 AC: 2208 AN: 235358 AF XY: 0.00938

Gnomad AFR exome AF: 0.0229

Gnomad AMR exome AF: 0.00363

Gnomad ASJ exome AF: 0.0192

Gnomad EAS exome AF: 0.00243

Gnomad FIN exome AF: 0.00842

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00843

GnomAD4 exome AF: 0.00998 AC: 14334 AN: 1435720 Hom.: 88 Cov.: 34 AF XY: 0.00996 AC XY: 7110 AN XY: 713612

African (AFR) AF: 0.0225 AC: 747 AN: 33150

American (AMR) AF: 0.00389 AC: 169 AN: 43396

Ashkenazi Jewish (ASJ) AF: 0.0179 AC: 459 AN: 25632

East Asian (EAS) AF: 0.00111 AC: 43 AN: 38798

South Asian (SAS) AF: 0.00466 AC: 391 AN: 83988

European-Finnish (FIN) AF: 0.00771 AC: 401 AN: 51980

Middle Eastern (MID) AF: 0.0106 AC: 49 AN: 4602

European-Non Finnish (NFE) AF: 0.0104 AC: 11379 AN: 1094954

Other (OTH) AF: 0.0118 AC: 696 AN: 59220

GnomAD4 genome AF: 0.0164 AC: 2295 AN: 139844 Hom.: 18 Cov.: 32 AF XY: 0.0167 AC XY: 1143 AN XY: 68330

African (AFR) AF: 0.0222 AC: 893 AN: 40174

American (AMR) AF: 0.00829 AC: 116 AN: 13998

Ashkenazi Jewish (ASJ) AF: 0.0180 AC: 56 AN: 3116

East Asian (EAS) AF: 0.00647 AC: 29 AN: 4480

South Asian (SAS) AF: 0.0148 AC: 61 AN: 4122

European-Finnish (FIN) AF: 0.0139 AC: 133 AN: 9550

Middle Eastern (MID) AF: 0.0153 AC: 4 AN: 262

European-Non Finnish (NFE) AF: 0.0155 AC: 950 AN: 61344

Other (OTH) AF: 0.0213 AC: 41 AN: 1926

Alfa AF: 0.0233 Hom.: 4

ESP6500AA AF: 0.0211 AC: 93

ESP6500EA AF: 0.0120 AC: 103

ExAC AF: 0.0122 AC: 1475

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital adrenal hyperplasia (1)
-	-	1	Deficiency of steroid 11-beta-monooxygenase (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.1
DANN	Benign	0.29
DEOGEN2	Benign	0.0072	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0015	N
LIST_S2	Benign	0.20	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.98	T
PhyloP100		-1.9
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.11
Sift	Benign	0.60	T
Sift4G	Benign	0.69	T
ClinPred		0.0045	T
GERP RS		-5.2
PromoterAI		-0.0048	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs61752794; hg19: chr8-143956748; COSMIC: COSV52829558;