NM_000196.4:c.108_125dupGGCGCTGGCGCTGCTGGC

Variant names:

• chr16-67431345-C-CCGCTGCTGGCGGCGCTGG
• rs1175206597
• NM_000196.4:c.108_125dupGGCGCTGGCGCTGCTGGC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_000196.4(HSD11B2):​c.108_125dupGGCGCTGGCGCTGCTGGC​(p.Ala42_Ala43insAlaLeuAlaLeuLeuAla) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000701 in 1,241,698 control chromosomes in the GnomAD database, including 1 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000074 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000070 (1 hom.)
• Consequence: HSD11B2 NM_000196.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.03
• 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)

ENSG00000261320 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000196.4.

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.108_125dupGGCGCTGGCGCTGCTGGC	p.Ala42_Ala43insAlaLeuAlaLeuLeuAla	disruptive_inframe_insertion	Exon 1 of 5	NP_000187.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD11B2	ENST00000326152.6	TSL:1 MANE Select	c.108_125dupGGCGCTGGCGCTGCTGGC	p.Ala42_Ala43insAlaLeuAlaLeuLeuAla	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000316786.5	P80365
	HSD11B2	ENST00000855497.1		c.108_125dupGGCGCTGGCGCTGCTGGC	p.Ala42_Ala43insAlaLeuAlaLeuLeuAla	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000525556.1
	HSD11B2	ENST00000855496.1		c.108_125dupGGCGCTGGCGCTGCTGGC	p.Ala42_Ala43insAlaLeuAlaLeuLeuAla	disruptive_inframe_insertion	Exon 1 of 5	ENSP00000525555.1

Frequencies

GnomAD3 genomes AF: 0.0000737 AC: 11 AN: 149328 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000898

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 51924 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000696 AC: 76 AN: 1092370 Hom.: 1 Cov.: 30 AF XY: 0.0000565 AC XY: 30 AN XY: 531392

African (AFR) AF: 0.0000462 AC: 1 AN: 21636

American (AMR) AF: 0.00 AC: 0 AN: 16168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15336

East Asian (EAS) AF: 0.00 AC: 0 AN: 17476

South Asian (SAS) AF: 0.00 AC: 0 AN: 40972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2820

European-Non Finnish (NFE) AF: 0.0000808 AC: 74 AN: 916224

Other (OTH) AF: 0.0000241 AC: 1 AN: 41408

GnomAD4 genome AF: 0.0000737 AC: 11 AN: 149328 Hom.: 0 Cov.: 31 AF XY: 0.0000824 AC XY: 6 AN XY: 72778

African (AFR) AF: 0.000122 AC: 5 AN: 41132

American (AMR) AF: 0.00 AC: 0 AN: 15028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000898 AC: 6 AN: 66848

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Apparent mineralocorticoid excess (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=73/27	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1175206597; hg19: chr16-67465248;