rs13306425

chr16-67435802-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_000196.4(HSD11B2):c.440G>A(p.Arg147His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,614,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R147R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: HSD11B2 NM_000196.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.09

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 Likely_benign. Variant got -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.03436008).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000126 (184/1461746) while in subpopulation EAS AF= 0.000756 (30/39700). AF 95% confidence interval is 0.000543. There are 0 homozygotes in gnomad4_exome. There are 89 alleles in male gnomad4_exome subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD11B2	NM_000196.4	c.440G>A	p.Arg147His	missense_variant	2/5	ENST00000326152.6
HSD11B2	XM_047434048.1	c.128G>A	p.Arg43His	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD11B2	ENST00000326152.6	c.440G>A	p.Arg147His	missense_variant	2/5	1	NM_000196.4	P1
HSD11B2	ENST00000567684.2	n.303G>A		non_coding_transcript_exon_variant	2/4	3
HSD11B2	ENST00000566606.1	c.*241G>A		3_prime_UTR_variant, NMD_transcript_variant	2/3	5

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000195 AC: 49 AN: 250992 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135762

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000203

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000126 AC: 184 AN: 1461746 Hom.: 0 Cov.: 34 AF XY: 0.000122 AC XY: 89 AN XY: 727162

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000756

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.000338

Gnomad4 NFE exome AF: 0.0000971

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000190 AC: 29 AN: 152294 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74452

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000772

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000167 Hom.: 0

Bravo AF: 0.000212

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2023	Variant summary: HSD11B2 c.440G>A (p.Arg147His) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 250992 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in HSD11B2 causing Apparent Mineralocorticoid Excess (0.0002 vs 0.0035), allowing no conclusion about variant significance. c.440G>A has been reported in the literature in individuals affected with hypertension without strong evidence of causality and at a similar frequency as the general population (Kamide_2006). This report does not provide unequivocal conclusions about association of the variant with Apparent Mineralocorticoid Excess. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 16778331). Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014, and classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 26, 2016	- -

Apparent mineralocorticoid excess Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 03, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	17
Dann	Benign	0.86
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.034	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.99	N
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.18
Sift	Benign	0.12	T
Sift4G	Benign	0.067	T
Polyphen		0.0080	B
Vest4		0.13
MVP		0.82
MPC		0.67
ClinPred		0.012	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.039
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs13306425; hg19: chr16-67469705; COSMIC: COSV52098989; COSMIC: COSV52098989;