rs12086634

Variant names:

• chr1-209706914-T-G
• rs12086634
• NM_005525.4:c.332-29T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005525.4(HSD11B1):​c.332-29T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 1,611,884 control chromosomes in the GnomAD database, including 33,020 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (2972 hom., cov: 32)
  • Exomes 𝑓: 0.20 (30048 hom.)
• Consequence: HSD11B1 NM_005525.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.07
• Publications: 42 publications found

Genes affected

HSD11B1 (HGNC:5208): (hydroxysteroid 11-beta dehydrogenase 1) The protein encoded by this gene is a microsomal enzyme that catalyzes the conversion of the stress hormone cortisol to the inactive metabolite cortisone. In addition, the encoded protein can catalyze the reverse reaction, the conversion of cortisone to cortisol. Too much cortisol can lead to central obesity, and a particular variation in this gene has been associated with obesity and insulin resistance in children. Mutations in this gene and H6PD (hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase)) are the cause of cortisone reductase deficiency. Alternate splicing results in multiple transcript variants encoding the same protein.[provided by RefSeq, May 2011]

HSD11B1-AS1 (HGNC:54053): (HSD11B1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 1-209706914-T-G is Benign according to our data. Variant chr1-209706914-T-G is described in ClinVar as Benign. ClinVar VariationId is 375729.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.207 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD11B1	NM_005525.4	c.332-29T>G		intron_variant	Intron 3 of 5	ENST00000367027.5	NP_005516.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD11B1	ENST00000367027.5	c.332-29T>G		intron_variant	Intron 3 of 5	1	NM_005525.4	ENSP00000355994.3

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29796 AN: 152074 Hom.: 2962 Cov.: 32

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.196

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.169

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.201

Gnomad OTH AF: 0.189

GnomAD2 exomes AF: 0.206 AC: 51796 AN: 250856 AF XY: 0.205

Gnomad AFR exome AF: 0.178

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.212

Gnomad EAS exome AF: 0.230

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.204

Gnomad OTH exome AF: 0.199

GnomAD4 exome AF: 0.200 AC: 292303 AN: 1459692 Hom.: 30048 Cov.: 32 AF XY: 0.199 AC XY: 144603 AN XY: 726312

African (AFR) AF: 0.174 AC: 5809 AN: 33436

American (AMR) AF: 0.208 AC: 9292 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.211 AC: 5520 AN: 26122

East Asian (EAS) AF: 0.183 AC: 7259 AN: 39680

South Asian (SAS) AF: 0.174 AC: 14963 AN: 86200

European-Finnish (FIN) AF: 0.263 AC: 14033 AN: 53408

Middle Eastern (MID) AF: 0.136 AC: 782 AN: 5764

European-Non Finnish (NFE) AF: 0.200 AC: 222246 AN: 1110048

Other (OTH) AF: 0.206 AC: 12399 AN: 60322

GnomAD4 genome AF: 0.196 AC: 29838 AN: 152192 Hom.: 2972 Cov.: 32 AF XY: 0.197 AC XY: 14646 AN XY: 74402

African (AFR) AF: 0.178 AC: 7397 AN: 41534

American (AMR) AF: 0.176 AC: 2694 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 729 AN: 3466

East Asian (EAS) AF: 0.217 AC: 1124 AN: 5178

South Asian (SAS) AF: 0.168 AC: 812 AN: 4822

European-Finnish (FIN) AF: 0.263 AC: 2787 AN: 10582

Middle Eastern (MID) AF: 0.130 AC: 38 AN: 292

European-Non Finnish (NFE) AF: 0.201 AC: 13675 AN: 68002

Other (OTH) AF: 0.190 AC: 403 AN: 2116

Alfa AF: 0.201 Hom.: 8365

Bravo AF: 0.193

Asia WGS AF: 0.208 AC: 724 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Cortisone reductase deficiency 2 Benign:1

-

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: research

The heterozygous c.331+94T>G variant in HSD11B1 has been identified in 3 individuals with cortisone reductase deficiency (PMID: 12858176). This variant is classified as benign for cortisone reductase deficiency because it has been identified in >25% of European (Finnish) chromosomes and 2719 total homozygotes by ExAC (http://gnomad.broadinstitute.org/). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.9
DANN	Benign	0.70
PhyloP100		-1.1
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: rs12086634; hg19: chr1-209880259; COSMIC: COSV54826450;