rs45483293

chr16-67436012-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000196.4(HSD11B2):c.534G>A(p.Glu178=) 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:4
• Conservation: PhyloP100: 4.44

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]

ACMG classification

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 586029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-67436012-G-A is described in Lovd as [Benign].
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD11B2	NM_000196.4	c.534G>A	p.Glu178=	synonymous_variant	3/5	ENST00000326152.6
HSD11B2	XM_047434048.1	c.222G>A	p.Glu74=	synonymous_variant	4/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD11B2	ENST00000326152.6	c.534G>A	p.Glu178=	synonymous_variant	3/5	1	NM_000196.4	P1
HSD11B2	ENST00000567684.2	n.397G>A		non_coding_transcript_exon_variant	3/4	3
HSD11B2	ENST00000566606.1	c.*335G>A		3_prime_UTR_variant, NMD_transcript_variant	3/3	5

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

GnomAD3 exomes AF: 0.0308 AC: 7749 AN: 251448 Hom.: 161 AF XY: 0.0316 AC XY: 4288 AN XY: 135906

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 SAS exome AF: 0.0110

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

Gnomad4 AFR exome AF: 0.00914

Gnomad4 AMR exome AF: 0.0233

Gnomad4 ASJ exome AF: 0.0618

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0115

Gnomad4 FIN exome AF: 0.0406

Gnomad4 NFE exome AF: 0.0411

Gnomad4 OTH exome AF: 0.0400

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

Gnomad4 AFR AF: 0.00871

Gnomad4 AMR AF: 0.0290

Gnomad4 ASJ AF: 0.0571

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00932

Gnomad4 FIN AF: 0.0358

Gnomad4 NFE AF: 0.0401

Gnomad4 OTH AF: 0.0430

Alfa AF: 0.0375 Hom.: 62

Bravo AF: 0.0271

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0423

EpiControl AF: 0.0461

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 30, 2018	- -

Apparent mineralocorticoid excess Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
Cadd	Benign	7.2
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs45483293; hg19: chr16-67469915; COSMIC: COSV52097990; COSMIC: COSV52097990;