chr16-67431328-ACCTGCGTCTGGGCCGCCCGCTGCTGGCGGCGCTGGCGCTGCTGGCCGCGCTCGACTGGCTGTGCCAGCGCCTGCTGCCCCCGCCGGCCGCACTCG-A

Position:

chr16-67431328-ACCTGCGTCTGGGCCGCCCGCTGCTGGCGGCGCTGGCGCTGCTGGCCGCGCTCGACTGGCTGTGCCAGCGCCTGCTGCCCCCGCCGGCCGCACTCG-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate

The NM_000196.4(HSD11B2):c.83_177del(p.Leu28ArgfsTer32) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000159 in 1,256,246 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 31)

Exomes 𝑓: 9.0e-7 ( 0 hom. )

Consequence

HSD11B2
NM_000196.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 2.88

Variant links:

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 9 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 16-67431328-ACCTGCGTCTGGGCCGCCCGCTGCTGGCGGCGCTGGCGCTGCTGGCCGCGCTCGACTGGCTGTGCCAGCGCCTGCTGCCCCCGCCGGCCGCACTCG-A is Pathogenic according to our data. Variant chr16-67431328-ACCTGCGTCTGGGCCGCCCGCTGCTGGCGGCGCTGGCGCTGCTGGCCGCGCTCGACTGGCTGTGCCAGCGCCTGCTGCCCCCGCCGGCCGCACTCG-A is described in ClinVar as [Pathogenic]. Clinvar id is 2033856.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD11B2	NM_000196.4 linkuse as main transcript	c.83_177del	p.Leu28ArgfsTer32	frameshift_variant	1/5	ENST00000326152.6	NP_000187.3
HSD11B2	XM_047434048.1 linkuse as main transcript	c.-48+552_-48+646del		intron_variant			XP_047290004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD11B2	ENST00000326152.6 linkuse as main transcript	c.83_177del	p.Leu28ArgfsTer32	frameshift_variant	1/5	1	NM_000196.4	ENSP00000316786	P1
	ENST00000567261.1 linkuse as main transcript	n.42_135+1del		splice_donor_variant, non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.00000669

AC:

AN:

149452

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.04e-7

AC:

AN:

1106794

Hom.:

AF XY:

0.00000185

AC XY:

AN XY:

539518

show subpopulations

Gnomad4 AFR exome

AF:

0.0000455

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000669

AC:

AN:

149452

Hom.:

Cov.:

AF XY:

0.0000137

AC XY:

AN XY:

72844

show subpopulations

Gnomad4 AFR

AF:

0.0000243

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2022

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with HSD11B2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Leu28Argfs*32) in the HSD11B2 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HSD11B2 are known to be pathogenic (PMID: 12860834, 15134813, 17314322). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over