rs4546

Variant names:

• chr8-142915137-G-A
• rs4546
• NM_000498.3:c.504C>T

Your query was ambiguous. Multiple possible variants found:

• chr8-142915137-G-A
• chr8-142915137-G-C
• chr8-142915137-G-T

Variant summary

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

The NM_000498.3(CYP11B2):​c.504C>T​(p.Phe168Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 1,612,206 control chromosomes in the GnomAD database, including 157,026 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12172 hom., cov: 31)
  • Exomes 𝑓: 0.44 (144854 hom.)
• Consequence: CYP11B2 NM_000498.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 1.58
• Publications: 20 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 8-142915137-G-A is Benign according to our data. Variant chr8-142915137-G-A is described in ClinVar as Benign. ClinVar VariationId is 362221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.58 with no splicing effect.
• 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.504C>T	p.Phe168Phe	synonymous	Exon 3 of 9	NP_000489.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYP11B2	ENST00000323110.2	TSL:1 MANE Select	c.504C>T	p.Phe168Phe	synonymous	Exon 3 of 9	ENSP00000325822.2
	CYP11B2	ENST00000945895.1		c.504C>T	p.Phe168Phe	synonymous	Exon 3 of 9	ENSP00000615954.1
	CYP11B2	ENST00000945896.1		c.504C>T	p.Phe168Phe	synonymous	Exon 3 of 9	ENSP00000615955.1

Frequencies

GnomAD3 genomes AF: 0.385 AC: 58465 AN: 151792 Hom.: 12166 Cov.: 31

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.429

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.298

Gnomad SAS AF: 0.417

Gnomad FIN AF: 0.479

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.451

Gnomad OTH AF: 0.418

GnomAD2 exomes AF: 0.424 AC: 105583 AN: 248894 AF XY: 0.431

Gnomad AFR exome AF: 0.224

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.548

Gnomad EAS exome AF: 0.292

Gnomad FIN exome AF: 0.494

Gnomad NFE exome AF: 0.446

Gnomad OTH exome AF: 0.442

GnomAD4 exome AF: 0.443 AC: 646392 AN: 1460298 Hom.: 144854 Cov.: 49 AF XY: 0.443 AC XY: 322145 AN XY: 726432

African (AFR) AF: 0.221 AC: 7401 AN: 33458

American (AMR) AF: 0.431 AC: 19187 AN: 44544

Ashkenazi Jewish (ASJ) AF: 0.549 AC: 14344 AN: 26122

East Asian (EAS) AF: 0.318 AC: 12597 AN: 39674

South Asian (SAS) AF: 0.432 AC: 37193 AN: 86126

European-Finnish (FIN) AF: 0.498 AC: 26527 AN: 53320

Middle Eastern (MID) AF: 0.470 AC: 2702 AN: 5754

European-Non Finnish (NFE) AF: 0.450 AC: 499723 AN: 1110964

Other (OTH) AF: 0.443 AC: 26718 AN: 60336

GnomAD4 genome AF: 0.385 AC: 58497 AN: 151908 Hom.: 12172 Cov.: 31 AF XY: 0.390 AC XY: 28956 AN XY: 74218

African (AFR) AF: 0.226 AC: 9394 AN: 41490

American (AMR) AF: 0.429 AC: 6555 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1879 AN: 3470

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

South Asian (SAS) AF: 0.419 AC: 2019 AN: 4824

European-Finnish (FIN) AF: 0.479 AC: 5053 AN: 10540

Middle Eastern (MID) AF: 0.425 AC: 124 AN: 292

European-Non Finnish (NFE) AF: 0.451 AC: 30601 AN: 67870

Other (OTH) AF: 0.415 AC: 875 AN: 2108

Alfa AF: 0.427 Hom.: 5859

Bravo AF: 0.375

Asia WGS AF: 0.314 AC: 1093 AN: 3476

EpiCase AF: 0.459

EpiControl AF: 0.459

ClinVar

ClinVar submissions as Germline

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 methyl oxidase type II deficiency (1)
-	-	1	Glucocorticoid-remediable aldosteronism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	7.8
DANN	Benign	0.75
PhyloP100		1.6
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4546; hg19: chr8-143996553; COSMIC: COSV59994442;