rs5479

Positions:

• chr16-67435830-C-A
• chr16-67435830-C-G
• chr16-67435830-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000196.4(HSD11B2):​c.468C>A​(p.Thr156=) 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

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 -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 id is 586028.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-67435830-C-A is described in Lovd as [Benign].
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD11B2	NM_000196.4	c.468C>A	p.Thr156=	synonymous_variant	2/5	ENST00000326152.6
HSD11B2	XM_047434048.1	c.156C>A	p.Thr52=	synonymous_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD11B2	ENST00000326152.6	c.468C>A	p.Thr156=	synonymous_variant	2/5	1	NM_000196.4	P1
HSD11B2	ENST00000567684.2	n.331C>A		non_coding_transcript_exon_variant	2/4	3
HSD11B2	ENST00000566606.1	c.*269C>A		3_prime_UTR_variant, NMD_transcript_variant	2/3	5

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

GnomAD3 exomes AF: 0.0542 AC: 13602 AN: 250788 Hom.: 596 AF XY: 0.0543 AC XY: 7365 AN XY: 135644

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 SAS exome AF: 0.0812

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

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.0380

Gnomad4 ASJ exome AF: 0.0629

Gnomad4 EAS exome AF: 0.00166

Gnomad4 SAS exome AF: 0.0762

Gnomad4 FIN exome AF: 0.0405

Gnomad4 NFE exome AF: 0.0421

Gnomad4 OTH exome AF: 0.0594

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

Gnomad4 AFR AF: 0.191

Gnomad4 AMR AF: 0.0562

Gnomad4 ASJ AF: 0.0576

Gnomad4 EAS AF: 0.00386

Gnomad4 SAS AF: 0.0709

Gnomad4 FIN AF: 0.0360

Gnomad4 NFE AF: 0.0413

Gnomad4 OTH AF: 0.0810

Alfa AF: 0.0496 Hom.: 349

Bravo AF: 0.0880

Asia WGS AF: 0.0530 AC: 182 AN: 3478

EpiCase AF: 0.0442

EpiControl AF: 0.0484

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Aug 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 22, 2019	This variant is associated with the following publications: (PMID: 16109323) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

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	-0.54
CADD	Benign	5.9
DANN	Benign	0.77

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: rs5479; hg19: chr16-67469733; COSMIC: COSV52099280; COSMIC: COSV52099280;