GeneBe

chr16-67431328-ACCTGCGTCTGGGCCGCCCGCTGCTGGCGGCGCTGGCGCTGCTGGCCGCGCTCGACTGGCTGTGCCAGCGCCTGCTGCCCCCGCCGGCCGCACTCG-A

Position:

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_177delTGCGTCTGGGCCGCCCGCTGCTGGCGGCGCTGGCGCTGCTGGCCGCGCTCGACTGGCTGTGCCAGCGCCTGCTGCCCCCGCCGGCCGCACTCGCC​(p.Leu28fs) 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]

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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
HSD11B2NM_000196.4 linkuse as main transcriptc.83_177delTGCGTCTGGGCCGCCCGCTGCTGGCGGCGCTGGCGCTGCTGGCCGCGCTCGACTGGCTGTGCCAGCGCCTGCTGCCCCCGCCGGCCGCACTCGCC p.Leu28fs frameshift_variant 1/5 ENST00000326152.6 NP_000187.3 P80365
HSD11B2XM_047434048.1 linkuse as main transcriptc.-48+552_-48+646delTGCGTCTGGGCCGCCCGCTGCTGGCGGCGCTGGCGCTGCTGGCCGCGCTCGACTGGCTGTGCCAGCGCCTGCTGCCCCCGCCGGCCGCACTCGCC intron_variant XP_047290004.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
HSD11B2ENST00000326152.6 linkuse as main transcriptc.83_177delTGCGTCTGGGCCGCCCGCTGCTGGCGGCGCTGGCGCTGCTGGCCGCGCTCGACTGGCTGTGCCAGCGCCTGCTGCCCCCGCCGGCCGCACTCGCC p.Leu28fs frameshift_variant 1/51 NM_000196.4 ENSP00000316786.5 P80365

Frequencies

GnomAD3 genomes
AF:
0.00000669
AC:
1
AN:
149452
Hom.:
0
Cov.:
31
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:
1
AN:
1106794
Hom.:
0
AF XY:
0.00000185
AC XY:
1
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:
1
AN:
149452
Hom.:
0
Cov.:
31
AF XY:
0.0000137
AC XY:
1
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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 03, 2022For 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.

Other links and lift over

dbSNP: rs2040931363; hg19: chr16-67465231; API