NM_000196.4:c.664+16dupC

Variant names:

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

Variant summary

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

The NM_000196.4(HSD11B2):​c.664+16dupC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,564,162 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: HSD11B2 NM_000196.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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-G-GC is Benign according to our data. Variant chr16-67436149-G-GC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 723515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.001 (151/150936) while in subpopulation EAS AF = 0.00293 (15/5118). AF 95% confidence interval is 0.00181. There are 0 homozygotes in GnomAd4. There are 78 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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.664+16dupC		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+7_664+8insC		splice_region intron	N/A	ENSP00000316786.5	P80365
	HSD11B2	ENST00000855497.1		c.664+7_664+8insC		splice_region intron	N/A	ENSP00000525556.1
	HSD11B2	ENST00000855496.1		c.637+7_637+8insC		splice_region intron	N/A	ENSP00000525555.1

Frequencies

GnomAD3 genomes AF: 0.000995 AC: 150 AN: 150828 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00292

Gnomad SAS AF: 0.00126

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000487

GnomAD2 exomes AF: 0.00340 AC: 715 AN: 210458 AF XY: 0.00197

Gnomad AFR exome AF: 0.00607

Gnomad AMR exome AF: 0.00116

Gnomad ASJ exome AF: 0.00212

Gnomad EAS exome AF: 0.00398

Gnomad FIN exome AF: 0.00122

Gnomad NFE exome AF: 0.00470

Gnomad OTH exome AF: 0.00319

GnomAD4 exome AF: 0.00143 AC: 2024 AN: 1413226 Hom.: 3 Cov.: 36 AF XY: 0.00142 AC XY: 999 AN XY: 703968

African (AFR) AF: 0.00188 AC: 61 AN: 32438

American (AMR) AF: 0.000981 AC: 43 AN: 43838

Ashkenazi Jewish (ASJ) AF: 0.0000788 AC: 2 AN: 25370

East Asian (EAS) AF: 0.00350 AC: 134 AN: 38324

South Asian (SAS) AF: 0.00119 AC: 101 AN: 84868

European-Finnish (FIN) AF: 0.00742 AC: 376 AN: 50646

Middle Eastern (MID) AF: 0.00108 AC: 6 AN: 5536

European-Non Finnish (NFE) AF: 0.00115 AC: 1231 AN: 1073960

Other (OTH) AF: 0.00120 AC: 70 AN: 58246

GnomAD4 genome AF: 0.00100 AC: 151 AN: 150936 Hom.: 0 Cov.: 31 AF XY: 0.00106 AC XY: 78 AN XY: 73722

African (AFR) AF: 0.00107 AC: 44 AN: 41212

American (AMR) AF: 0.000198 AC: 3 AN: 15148

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00293 AC: 15 AN: 5118

South Asian (SAS) AF: 0.00126 AC: 6 AN: 4770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10390

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

European-Non Finnish (NFE) AF: 0.00121 AC: 82 AN: 67586

Other (OTH) AF: 0.000482 AC: 1 AN: 2074

Alfa AF: 0.00260 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Apparent mineralocorticoid excess (1)
-	-	1	not provided (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; COSMIC: COSV52097001; COSMIC: COSV52097001;