16-67436149-GCC-GC

Variant names:

• chr16-67436149-GC-G
• rs72650121
• NM_000196.4:c.664+16delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The ENST00000326152.6(HSD11B2):​c.664+8delC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,578,856 control chromosomes in the GnomAD database, including 23 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0068 (7 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (16 hom.)
• Consequence: HSD11B2 ENST00000326152.6 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.349
• Publications: 0 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 -16 ACMG points.

• BP6: Variant 16-67436149-GC-G is Benign according to our data. Variant chr16-67436149-GC-G is described in ClinVar as Benign. ClinVar VariationId is 586030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00677 (1022/150950) while in subpopulation AFR AF = 0.0216 (889/41210). AF 95% confidence interval is 0.0204. There are 7 homozygotes in GnomAd4. There are 493 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000326152.6. 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.664+16delC		intron	N/A	NP_000187.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD11B2	ENST00000326152.6	TSL:1 MANE Select	c.664+8delC		splice_region intron	N/A	ENSP00000316786.5	P80365
	HSD11B2	ENST00000855497.1		c.664+8delC		splice_region intron	N/A	ENSP00000525556.1
	HSD11B2	ENST00000855496.1		c.637+8delC		splice_region intron	N/A	ENSP00000525555.1

Frequencies

GnomAD3 genomes AF: 0.00678 AC: 1023 AN: 150842 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00311

Gnomad ASJ AF: 0.00728

Gnomad EAS AF: 0.000390

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000680

Gnomad OTH AF: 0.00536

GnomAD2 exomes AF: 0.00226 AC: 476 AN: 210458 AF XY: 0.00181

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.000896

Gnomad ASJ exome AF: 0.00580

Gnomad EAS exome AF: 0.000321

Gnomad FIN exome AF: 0.000489

Gnomad NFE exome AF: 0.000733

Gnomad OTH exome AF: 0.00113

GnomAD4 exome AF: 0.00120 AC: 1717 AN: 1427906 Hom.: 16 Cov.: 36 AF XY: 0.00113 AC XY: 805 AN XY: 710870

African (AFR) AF: 0.0240 AC: 785 AN: 32756

American (AMR) AF: 0.00104 AC: 46 AN: 44090

Ashkenazi Jewish (ASJ) AF: 0.00457 AC: 117 AN: 25590

East Asian (EAS) AF: 0.000129 AC: 5 AN: 38632

South Asian (SAS) AF: 0.000211 AC: 18 AN: 85232

European-Finnish (FIN) AF: 0.000274 AC: 14 AN: 51110

Middle Eastern (MID) AF: 0.00215 AC: 12 AN: 5584

European-Non Finnish (NFE) AF: 0.000539 AC: 585 AN: 1086072

Other (OTH) AF: 0.00229 AC: 135 AN: 58840

GnomAD4 genome AF: 0.00677 AC: 1022 AN: 150950 Hom.: 7 Cov.: 31 AF XY: 0.00669 AC XY: 493 AN XY: 73728

African (AFR) AF: 0.0216 AC: 889 AN: 41210

American (AMR) AF: 0.00310 AC: 47 AN: 15146

Ashkenazi Jewish (ASJ) AF: 0.00728 AC: 25 AN: 3436

East Asian (EAS) AF: 0.000391 AC: 2 AN: 5118

South Asian (SAS) AF: 0.000419 AC: 2 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000681 AC: 46 AN: 67596

Other (OTH) AF: 0.00530 AC: 11 AN: 2074

Alfa AF: 0.00121 Hom.: 0

Bravo AF: 0.00789

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	HSD11B2-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.35
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs72650121; hg19: chr16-67470052;