rs45598932

Variant names:

• chr16-67430908-G-A
• rs45598932
• ENST00000567261.1:n.234C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000567261.1(ENSG00000261320):​n.234C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0258 in 152,026 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (51 hom., cov: 32)
  • Exomes 𝑓: 0.020 (1 hom.)
• Consequence: ENSG00000261320 ENST00000567261.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.502
• Publications: 6 publications found

Genes affected

ENSG00000261320 (HGNC:):

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: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 16-67430908-G-A is Benign according to our data. Variant chr16-67430908-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1208628.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0259 (3869/149426) while in subpopulation NFE AF = 0.031 (2081/67200). AF 95% confidence interval is 0.0299. There are 51 homozygotes in GnomAd4. There are 1813 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 51 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD11B2	XM_047434048.1	c.-48+129G>A		intron_variant	Intron 2 of 5		XP_047290004.1
HSD11B2	NM_000196.4	c.-341G>A		upstream_gene_variant		ENST00000326152.6	NP_000187.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000261320	ENST00000567261.1	n.234C>T		non_coding_transcript_exon_variant	Exon 2 of 2	3
HSD11B2	ENST00000567684.2	n.128+129G>A		intron_variant	Intron 1 of 3	3
HSD11B2	ENST00000326152.6	c.-341G>A		upstream_gene_variant		1	NM_000196.4	ENSP00000316786.5
HSD11B2	ENST00000569303.1	n.-214G>A		upstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.0259 AC: 3863 AN: 149336 Hom.: 51 Cov.: 32

Gnomad AFR AF: 0.0275

Gnomad AMI AF: 0.0312

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.0141

Gnomad EAS AF: 0.00828

Gnomad SAS AF: 0.0291

Gnomad FIN AF: 0.00951

Gnomad MID AF: 0.0390

Gnomad NFE AF: 0.0309

Gnomad OTH AF: 0.0300

GnomAD4 exome AF: 0.0204 AC: 53 AN: 2600 Hom.: 1 Cov.: 0 AF XY: 0.0208 AC XY: 29 AN XY: 1392

African (AFR) AF: 0.0326 AC: 3 AN: 92

American (AMR) AF: 0.00 AC: 0 AN: 86

Ashkenazi Jewish (ASJ) AF: 0.0256 AC: 2 AN: 78

East Asian (EAS) AF: 0.00 AC: 0 AN: 130

South Asian (SAS) AF: 0.00 AC: 0 AN: 26

European-Finnish (FIN) AF: 0.00532 AC: 1 AN: 188

Middle Eastern (MID) AF: 0.0500 AC: 1 AN: 20

European-Non Finnish (NFE) AF: 0.0237 AC: 43 AN: 1816

Other (OTH) AF: 0.0183 AC: 3 AN: 164

GnomAD4 genome AF: 0.0259 AC: 3869 AN: 149426 Hom.: 51 Cov.: 32 AF XY: 0.0249 AC XY: 1813 AN XY: 72858

African (AFR) AF: 0.0275 AC: 1122 AN: 40786

American (AMR) AF: 0.0160 AC: 240 AN: 15040

Ashkenazi Jewish (ASJ) AF: 0.0141 AC: 48 AN: 3416

East Asian (EAS) AF: 0.00851 AC: 42 AN: 4936

South Asian (SAS) AF: 0.0289 AC: 135 AN: 4678

European-Finnish (FIN) AF: 0.00951 AC: 96 AN: 10096

Middle Eastern (MID) AF: 0.0350 AC: 10 AN: 286

European-Non Finnish (NFE) AF: 0.0310 AC: 2081 AN: 67200

Other (OTH) AF: 0.0321 AC: 67 AN: 2090

Alfa AF: 0.0305 Hom.: 24

Bravo AF: 0.0258

Asia WGS AF: 0.0290 AC: 99 AN: 3466

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 26, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 17551100) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.8
DANN	Benign	0.92
PhyloP100		0.50
PromoterAI		-0.036	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs45598932; hg19: chr16-67464811; COSMIC: COSV58204050;