rs4545

Variant names:

• chr8-142912625-C-T
• rs4545
• NM_000498.3:c.1303G>A
• CYP11B2 p.Gly435Ser

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000498.3(CYP11B2):​c.1303G>A​(p.Gly435Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0461 in 1,614,188 control chromosomes in the GnomAD database, including 8,072 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. Synonymous variant affecting the same amino acid position (i.e. G435G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.054 (875 hom., cov: 32)
  • Exomes 𝑓: 0.045 (7197 hom.)
• Consequence: CYP11B2 NM_000498.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.72
• Publications: 37 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=9.875816E-5).
• BP6: Variant 8-142912625-C-T is Benign according to our data. Variant chr8-142912625-C-T is described in ClinVar as Benign. ClinVar VariationId is 362192.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.481 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.1303G>A	p.Gly435Ser	missense	Exon 8 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.1303G>A	p.Gly435Ser	missense	Exon 8 of 9	ENSP00000325822.2	P19099
	CYP11B2	ENST00000945895.1		c.1372G>A	p.Gly458Ser	missense	Exon 8 of 9	ENSP00000615954.1
	CYP11B2	ENST00000945896.1		c.1291G>A	p.Gly431Ser	missense	Exon 8 of 9	ENSP00000615955.1

Frequencies

GnomAD3 genomes AF: 0.0541 AC: 8233 AN: 152182 Hom.: 871 Cov.: 32

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.109

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.496

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.0493

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0196

Gnomad OTH AF: 0.0574

GnomAD2 exomes AF: 0.0918 AC: 23095 AN: 251444 AF XY: 0.0892

Gnomad AFR exome AF: 0.0271

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.0333

Gnomad EAS exome AF: 0.505

Gnomad FIN exome AF: 0.0529

Gnomad NFE exome AF: 0.0192

Gnomad OTH exome AF: 0.0626

GnomAD4 exome AF: 0.0453 AC: 66194 AN: 1461886 Hom.: 7197 Cov.: 40 AF XY: 0.0478 AC XY: 34750 AN XY: 727246

African (AFR) AF: 0.0230 AC: 770 AN: 33480

American (AMR) AF: 0.133 AC: 5952 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0321 AC: 838 AN: 26136

East Asian (EAS) AF: 0.503 AC: 19976 AN: 39700

South Asian (SAS) AF: 0.146 AC: 12573 AN: 86258

European-Finnish (FIN) AF: 0.0508 AC: 2716 AN: 53420

Middle Eastern (MID) AF: 0.0324 AC: 187 AN: 5768

European-Non Finnish (NFE) AF: 0.0176 AC: 19622 AN: 1112006

Other (OTH) AF: 0.0589 AC: 3560 AN: 60394

GnomAD4 genome AF: 0.0542 AC: 8251 AN: 152302 Hom.: 875 Cov.: 32 AF XY: 0.0614 AC XY: 4572 AN XY: 74460

African (AFR) AF: 0.0275 AC: 1143 AN: 41576

American (AMR) AF: 0.109 AC: 1674 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3472

East Asian (EAS) AF: 0.497 AC: 2561 AN: 5156

South Asian (SAS) AF: 0.156 AC: 754 AN: 4830

European-Finnish (FIN) AF: 0.0493 AC: 524 AN: 10622

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.0197 AC: 1337 AN: 68026

Other (OTH) AF: 0.0587 AC: 124 AN: 2114

Alfa AF: 0.0353 Hom.: 1371

Bravo AF: 0.0561

Asia WGS AF: 0.273 AC: 948 AN: 3478

EpiCase AF: 0.0147

EpiControl AF: 0.0160

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Corticosterone 18-monooxygenase deficiency (2)
-	-	2	Corticosterone methyloxidase type 2 deficiency (2)
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	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	0.075
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	0.97
DANN	Benign	0.76
DEOGEN2	Benign	0.081	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.000099	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.23	N
PhyloP100		-1.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.65	N
REVEL	Benign	0.18
Sift	Benign	0.43	T
Sift4G	Benign	0.56	T
Varity_R		0.089
gMVP		0.62
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4545;

hg19: chr8-143994041;

COSMIC: COSV59995205;