rs45483293

Variant names:

• chr16-67436012-G-A
• rs45483293
• NM_000196.4:c.534G>A

Variant summary

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

The NM_000196.4(HSD11B2):​c.534G>A​(p.Glu178Glu) variant causes a synonymous change. The variant allele was found at a frequency of 0.0367 in 1,614,214 control chromosomes in the GnomAD database, including 1,272 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (76 hom., cov: 32)
  • Exomes 𝑓: 0.037 (1196 hom.)
• Consequence: HSD11B2 NM_000196.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.44
• Publications: 29 publications found

Genes affected

HSD11B2 (HGNC:5209): (hydroxysteroid 11-beta dehydrogenase 2) There are at least two isozymes of the corticosteroid 11-beta-dehydrogenase, a microsomal enzyme complex responsible for the interconversion of cortisol and cortisone. The type I isozyme has both 11-beta-dehydrogenase (cortisol to cortisone) and 11-oxoreductase (cortisone to cortisol) activities. The type II isozyme, encoded by this gene, has only 11-beta-dehydrogenase activity. In aldosterone-selective epithelial tissues such as the kidney, the type II isozyme catalyzes the glucocorticoid cortisol to the inactive metabolite cortisone, thus preventing illicit activation of the mineralocorticoid receptor. In tissues that do not express the mineralocorticoid receptor, such as the placenta and testis, it protects cells from the growth-inhibiting and/or pro-apoptotic effects of cortisol, particularly during embryonic development. Mutations in this gene cause the syndrome of apparent mineralocorticoid excess and hypertension. [provided by RefSeq, Feb 2010]

HSD11B2 Gene-Disease associations (from GenCC):

• apparent mineralocorticoid excess

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 16-67436012-G-A is Benign according to our data. Variant chr16-67436012-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 586029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000196.4. 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
	HSD11B2	NM_000196.4	MANE Select	c.534G>A	p.Glu178Glu	synonymous	Exon 3 of 5	NP_000187.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD11B2	ENST00000326152.6	TSL:1 MANE Select	c.534G>A	p.Glu178Glu	synonymous	Exon 3 of 5	ENSP00000316786.5	P80365
	HSD11B2	ENST00000855497.1		c.534G>A	p.Glu178Glu	synonymous	Exon 3 of 5	ENSP00000525556.1
	HSD11B2	ENST00000855496.1		c.507G>A	p.Glu169Glu	synonymous	Exon 3 of 5	ENSP00000525555.1

Frequencies

GnomAD3 genomes AF: 0.0286 AC: 4352 AN: 152224 Hom.: 76 Cov.: 32

Gnomad AFR AF: 0.00871

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0290

Gnomad ASJ AF: 0.0571

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00931

Gnomad FIN AF: 0.0358

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0401

Gnomad OTH AF: 0.0435

GnomAD2 exomes AF: 0.0308 AC: 7749 AN: 251448 AF XY: 0.0316

Gnomad AFR exome AF: 0.00812

Gnomad AMR exome AF: 0.0229

Gnomad ASJ exome AF: 0.0601

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0362

Gnomad NFE exome AF: 0.0426

Gnomad OTH exome AF: 0.0406

GnomAD4 exome AF: 0.0375 AC: 54814 AN: 1461872 Hom.: 1196 Cov.: 35 AF XY: 0.0369 AC XY: 26831 AN XY: 727240

African (AFR) AF: 0.00914 AC: 306 AN: 33480

American (AMR) AF: 0.0233 AC: 1041 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0618 AC: 1615 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0115 AC: 990 AN: 86258

European-Finnish (FIN) AF: 0.0406 AC: 2166 AN: 53410

Middle Eastern (MID) AF: 0.0933 AC: 538 AN: 5768

European-Non Finnish (NFE) AF: 0.0411 AC: 45739 AN: 1112000

Other (OTH) AF: 0.0400 AC: 2417 AN: 60396

GnomAD4 genome AF: 0.0285 AC: 4348 AN: 152342 Hom.: 76 Cov.: 32 AF XY: 0.0274 AC XY: 2043 AN XY: 74488

African (AFR) AF: 0.00871 AC: 362 AN: 41584

American (AMR) AF: 0.0290 AC: 444 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.0571 AC: 198 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.00932 AC: 45 AN: 4828

European-Finnish (FIN) AF: 0.0358 AC: 381 AN: 10628

Middle Eastern (MID) AF: 0.133 AC: 39 AN: 294

European-Non Finnish (NFE) AF: 0.0401 AC: 2731 AN: 68022

Other (OTH) AF: 0.0430 AC: 91 AN: 2116

Alfa AF: 0.0375 Hom.: 63

Bravo AF: 0.0271

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0423

EpiControl AF: 0.0461

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	Apparent mineralocorticoid excess (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	7.2
DANN	Benign	0.79
PhyloP100		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs45483293; hg19: chr16-67469915; COSMIC: COSV52097990; COSMIC: COSV52097990;