Genetic Variant HSD11B2:p.Ala42Gly (chr16-67431373-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000196.4(HSD11B2):c.125C>G(p.Ala42Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A42T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HSD11B2
NM_000196.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.00

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:

ENSG00000261320 (HGNC:):

ENSG00000261320 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSD11B2	NM_000196.4 link	c.125C>G	p.Ala42Gly	missense_variant	Exon 1 of 5	ENST00000326152.6	NP_000187.3	P80365
HSD11B2	XM_047434048.1 link	c.-48+594C>G		intron_variant	Intron 2 of 5		XP_047290004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSD11B2	ENST00000326152.6 link	c.125C>G	p.Ala42Gly	missense_variant	Exon 1 of 5	1	NM_000196.4	ENSP00000316786.5		P80365

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1102590

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

535954

Gnomad4 AFR exome

AF:

0.00

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

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Apparent mineralocorticoid excess

Uncertain:1

Mar 26, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Uncertain

0.017

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.36

Eigen

Benign

0.013

Eigen_PC

Benign

0.031

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.65

M_CAP

Pathogenic

1.0

MetaRNN

Uncertain

0.58

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.0

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.74

REVEL

Benign

0.23

Sift

Benign

0.29

Sift4G

Benign

0.46

Polyphen

0.99

Vest4

0.34

MutPred

0.33

Loss of stability (P = 0.1082);

MVP

0.90

MPC

1.4

ClinPred

0.74

GERP RS

3.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.19

gMVP

0.29

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

Publications

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over