16-67435830-C-A

Variant names:

• chr16-67435830-C-A
• rs5479
• NM_000196.4:c.468C>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_000196.4(HSD11B2):​c.468C>A​(p.Thr156Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0513 in 1,613,970 control chromosomes in the GnomAD database, including 3,250 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T156T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.084 (873 hom., cov: 32)
  • Exomes 𝑓: 0.048 (2377 hom.)
• Consequence: HSD11B2 NM_000196.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.28
• Publications: 32 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 16-67435830-C-A is Benign according to our data. Variant chr16-67435830-C-A is described in ClinVar as Benign. ClinVar VariationId is 586028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.28 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 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.468C>A	p.Thr156Thr	synonymous	Exon 2 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.468C>A	p.Thr156Thr	synonymous	Exon 2 of 5	ENSP00000316786.5	P80365
	HSD11B2	ENST00000855497.1		c.468C>A	p.Thr156Thr	synonymous	Exon 2 of 5	ENSP00000525556.1
	HSD11B2	ENST00000855496.1		c.468C>A	p.Thr156Thr	synonymous	Exon 2 of 5	ENSP00000525555.1

Frequencies

GnomAD3 genomes AF: 0.0841 AC: 12787 AN: 152124 Hom.: 870 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0562

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.00385

Gnomad SAS AF: 0.0712

Gnomad FIN AF: 0.0360

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.0413

Gnomad OTH AF: 0.0813

GnomAD2 exomes AF: 0.0542 AC: 13602 AN: 250788 AF XY: 0.0543

Gnomad AFR exome AF: 0.193

Gnomad AMR exome AF: 0.0363

Gnomad ASJ exome AF: 0.0616

Gnomad EAS exome AF: 0.00250

Gnomad FIN exome AF: 0.0362

Gnomad NFE exome AF: 0.0439

Gnomad OTH exome AF: 0.0526

GnomAD4 exome AF: 0.0479 AC: 69959 AN: 1461728 Hom.: 2377 Cov.: 35 AF XY: 0.0482 AC XY: 35083 AN XY: 727178

African (AFR) AF: 0.201 AC: 6729 AN: 33470

American (AMR) AF: 0.0380 AC: 1698 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0629 AC: 1644 AN: 26136

East Asian (EAS) AF: 0.00166 AC: 66 AN: 39698

South Asian (SAS) AF: 0.0762 AC: 6571 AN: 86256

European-Finnish (FIN) AF: 0.0405 AC: 2159 AN: 53300

Middle Eastern (MID) AF: 0.114 AC: 656 AN: 5768

European-Non Finnish (NFE) AF: 0.0421 AC: 46846 AN: 1111986

Other (OTH) AF: 0.0594 AC: 3590 AN: 60392

GnomAD4 genome AF: 0.0841 AC: 12801 AN: 152242 Hom.: 873 Cov.: 32 AF XY: 0.0825 AC XY: 6142 AN XY: 74452

African (AFR) AF: 0.191 AC: 7910 AN: 41510

American (AMR) AF: 0.0562 AC: 859 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0576 AC: 200 AN: 3470

East Asian (EAS) AF: 0.00386 AC: 20 AN: 5182

South Asian (SAS) AF: 0.0709 AC: 342 AN: 4826

European-Finnish (FIN) AF: 0.0360 AC: 382 AN: 10612

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.0413 AC: 2812 AN: 68026

Other (OTH) AF: 0.0810 AC: 171 AN: 2112

Alfa AF: 0.0545 Hom.: 583

Bravo AF: 0.0880

Asia WGS AF: 0.0530 AC: 182 AN: 3478

EpiCase AF: 0.0442

EpiControl AF: 0.0484

ClinVar

ClinVar submissions

Significance: 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	-0.54
CADD	Benign	5.9
DANN	Benign	0.77
PhyloP100		-1.3
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: rs5479; hg19: chr16-67469733; COSMIC: COSV52099280; COSMIC: COSV52099280;