rs4536

Variant names:

• chr8-142914345-C-T
• rs4536
• NM_000498.3:c.873G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-142914345-C-T
• chr8-142914345-C-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_000498.3(CYP11B2):​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 0.952 in 1,613,702 control chromosomes in the GnomAD database, including 737,901 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67590 hom., cov: 32)
  • Exomes 𝑓: 0.95 (670311 hom.)
• Consequence: CYP11B2 NM_000498.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -5.37
• Publications: 31 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=-0.96).
• BP6: Variant 8-142914345-C-T is Benign according to our data. Variant chr8-142914345-C-T is described in ClinVar as Benign. ClinVar VariationId is 362207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.37 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.974 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.873G>A	p.Ala291Ala	synonymous	Exon 5 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.873G>A	p.Ala291Ala	synonymous	Exon 5 of 9	ENSP00000325822.2	P19099
	CYP11B2	ENST00000945895.1		c.873G>A	p.Ala291Ala	synonymous	Exon 5 of 9	ENSP00000615954.1
	CYP11B2	ENST00000945896.1		c.873G>A	p.Ala291Ala	synonymous	Exon 5 of 9	ENSP00000615955.1

Frequencies

GnomAD3 genomes AF: 0.938 AC: 142591 AN: 152082 Hom.: 67546 Cov.: 32

Gnomad AFR AF: 0.947

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.889

Gnomad ASJ AF: 0.963

Gnomad EAS AF: 0.482

Gnomad SAS AF: 0.838

Gnomad FIN AF: 0.950

Gnomad MID AF: 0.981

Gnomad NFE AF: 0.980

Gnomad OTH AF: 0.935

GnomAD2 exomes AF: 0.905 AC: 227291 AN: 251258 AF XY: 0.908

Gnomad AFR exome AF: 0.946

Gnomad AMR exome AF: 0.858

Gnomad ASJ exome AF: 0.967

Gnomad EAS exome AF: 0.477

Gnomad FIN exome AF: 0.947

Gnomad NFE exome AF: 0.981

Gnomad OTH exome AF: 0.935

GnomAD4 exome AF: 0.954 AC: 1393549 AN: 1461502 Hom.: 670311 Cov.: 41 AF XY: 0.951 AC XY: 691593 AN XY: 727074

African (AFR) AF: 0.951 AC: 31826 AN: 33462

American (AMR) AF: 0.864 AC: 38619 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.968 AC: 25293 AN: 26132

East Asian (EAS) AF: 0.487 AC: 19331 AN: 39678

South Asian (SAS) AF: 0.855 AC: 73683 AN: 86224

European-Finnish (FIN) AF: 0.949 AC: 50680 AN: 53416

Middle Eastern (MID) AF: 0.966 AC: 5574 AN: 5768

European-Non Finnish (NFE) AF: 0.982 AC: 1092019 AN: 1111732

Other (OTH) AF: 0.936 AC: 56524 AN: 60386

GnomAD4 genome AF: 0.938 AC: 142691 AN: 152200 Hom.: 67590 Cov.: 32 AF XY: 0.931 AC XY: 69225 AN XY: 74390

African (AFR) AF: 0.947 AC: 39317 AN: 41522

American (AMR) AF: 0.889 AC: 13584 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.963 AC: 3340 AN: 3470

East Asian (EAS) AF: 0.481 AC: 2468 AN: 5130

South Asian (SAS) AF: 0.839 AC: 4045 AN: 4824

European-Finnish (FIN) AF: 0.950 AC: 10082 AN: 10608

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.980 AC: 66679 AN: 68036

Other (OTH) AF: 0.934 AC: 1976 AN: 2116

Alfa AF: 0.955 Hom.: 41722

Bravo AF: 0.935

Asia WGS AF: 0.699 AC: 2435 AN: 3478

EpiCase AF: 0.985

EpiControl AF: 0.984

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 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	-0.96
CADD	Benign	0.023
DANN	Benign	0.63
PhyloP100		-5.4
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: rs4536; hg19: chr8-143995761; COSMIC: COSV59998409;