rs4539

Variant names:

• chr8-142915123-T-C
• rs4539
• NM_000498.3:c.518A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000498.3(CYP11B2):​c.518A>G​(p.Lys173Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.386 in 151,876 control chromosomes in the GnomAD database, including 12,203 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.39 (12203 hom., cov: 31)
  • Exomes 𝑓: 0.44 (144826 hom.)
  • Failed GnomAD Quality Control
• Consequence: CYP11B2 NM_000498.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -0.530
• Publications: 63 publications found

Genes affected

CYP11B2 (HGNC:2592): (cytochrome P450 family 11 subfamily B member 2) 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. The enzyme has steroid 18-hydroxylase activity to synthesize aldosterone and 18-oxocortisol as well as steroid 11 beta-hydroxylase activity. Mutations in this gene cause corticosterone methyl oxidase deficiency. [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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000498.3
• BP4: Computational evidence support a benign effect (MetaRNN=3.9825718E-5).
• BP6: Variant 8-142915123-T-C is Benign according to our data. Variant chr8-142915123-T-C is described in ClinVar as Benign. ClinVar VariationId is 362220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000498.3. 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
	CYP11B2	NM_000498.3	MANE Select	c.518A>G	p.Lys173Arg	missense	Exon 3 of 9	NP_000489.3	P19099

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B2	ENST00000323110.2	TSL:1 MANE Select	c.518A>G	p.Lys173Arg	missense	Exon 3 of 9	ENSP00000325822.2	P19099
	CYP11B2	ENST00000945895.1		c.518A>G	p.Lys173Arg	missense	Exon 3 of 9	ENSP00000615954.1
	CYP11B2	ENST00000945896.1		c.518A>G	p.Lys173Arg	missense	Exon 3 of 9	ENSP00000615955.1

Frequencies

GnomAD3 genomes AF: 0.386 AC: 58596 AN: 151760 Hom.: 12195 Cov.: 31

Gnomad AFR AF: 0.229

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.430

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.418

Gnomad FIN AF: 0.480

Gnomad MID AF: 0.440

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.420

GnomAD2 exomes AF: 0.424 AC: 105290 AN: 248332 AF XY: 0.431

Gnomad AFR exome AF: 0.227

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.291

Gnomad FIN exome AF: 0.493

Gnomad NFE exome AF: 0.446

Gnomad OTH exome AF: 0.443

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.443 AC: 646367 AN: 1459998 Hom.: 144826 Cov.: 47 AF XY: 0.444 AC XY: 322074 AN XY: 726180

African (AFR) AF: 0.224 AC: 7511 AN: 33464

American (AMR) AF: 0.431 AC: 19173 AN: 44520

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 14342 AN: 26116

East Asian (EAS) AF: 0.318 AC: 12601 AN: 39674

South Asian (SAS) AF: 0.432 AC: 37175 AN: 86068

European-Finnish (FIN) AF: 0.498 AC: 26524 AN: 53314

Middle Eastern (MID) AF: 0.470 AC: 2706 AN: 5752

European-Non Finnish (NFE) AF: 0.450 AC: 499602 AN: 1110756

Other (OTH) AF: 0.443 AC: 26733 AN: 60334

GnomAD4 genome AF: 0.386 AC: 58630 AN: 151876 Hom.: 12203 Cov.: 31 AF XY: 0.391 AC XY: 29016 AN XY: 74202

African (AFR) AF: 0.229 AC: 9507 AN: 41482

American (AMR) AF: 0.430 AC: 6559 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1877 AN: 3468

East Asian (EAS) AF: 0.297 AC: 1524 AN: 5134

South Asian (SAS) AF: 0.420 AC: 2026 AN: 4828

European-Finnish (FIN) AF: 0.480 AC: 5055 AN: 10526

Middle Eastern (MID) AF: 0.428 AC: 125 AN: 292

European-Non Finnish (NFE) AF: 0.451 AC: 30604 AN: 67862

Other (OTH) AF: 0.417 AC: 880 AN: 2110

Alfa AF: 0.428 Hom.: 6085

Bravo AF: 0.376

ESP6500AA AF: 0.236 AC: 1038

ESP6500EA AF: 0.449 AC: 3857

ExAC AF: 0.417 AC: 50583

EpiCase AF: 0.459

EpiControl AF: 0.459

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Corticosterone 18-monooxygenase deficiency (2)
-	-	2	Corticosterone methyloxidase type 2 deficiency (2)
-	-	1	Corticosterone 18-monooxygenase deficiency;C3463917:Corticosterone methyloxidase type 2 deficiency (1)
-	-	1	Corticosterone methyl oxidase type II deficiency (1)
-	-	1	Glucocorticoid-remediable aldosteronism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	0.20
DANN	Benign	0.36
DEOGEN2	Benign	0.092	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.000040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.33	N
PhyloP100		-0.53
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.34	N
REVEL	Benign	0.035
Sift	Benign	0.62	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.052
MPC		0.20
ClinPred		0.0081	T
GERP RS		-4.2
Varity_R		0.10
gMVP		0.64
Mutation Taster		=96/4	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: rs4539; hg19: chr8-143996539; COSMIC: COSV59995600;