16-67431420-C-T

Variant names:

• chr16-67431420-C-T
• rs2040932475
• NM_000196.4:c.172C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000196.4(HSD11B2):​c.172C>T​(p.Leu58Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000261 in 1,150,016 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000026 (0 hom.)
• Consequence: HSD11B2 NM_000196.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.178
• 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.

• PM2: Very rare variant in population databases, with high coverage

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.172C>T	p.Leu58Phe	missense	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.172C>T	p.Leu58Phe	missense	Exon 1 of 5	ENSP00000316786.5	P80365
	HSD11B2	ENST00000855497.1		c.172C>T	p.Leu58Phe	missense	Exon 1 of 5	ENSP00000525556.1
	HSD11B2	ENST00000855496.1		c.172C>T	p.Leu58Phe	missense	Exon 1 of 5	ENSP00000525555.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000261 AC: 3 AN: 1150016 Hom.: 0 Cov.: 31 AF XY: 0.00000357 AC XY: 2 AN XY: 559722

African (AFR) AF: 0.00 AC: 0 AN: 22874

American (AMR) AF: 0.00 AC: 0 AN: 11554

Ashkenazi Jewish (ASJ) AF: 0.000124 AC: 2 AN: 16074

East Asian (EAS) AF: 0.00 AC: 0 AN: 25054

South Asian (SAS) AF: 0.00 AC: 0 AN: 40618

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25008

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3096

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 960130

Other (OTH) AF: 0.00 AC: 0 AN: 45608

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	0.057
Eigen_PC	Benign	0.074
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.50	D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.18
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.34
Sift	Benign	0.058	T
Sift4G	Benign	0.063	T
Polyphen		0.97	D
Vest4		0.20
MutPred		0.45		Loss of glycosylation at P55 (P = 0.1334)
MVP		0.92
MPC		1.4
ClinPred		0.67	D
GERP RS		2.8
PromoterAI		0.012	Neutral
Varity_R		0.21
gMVP		0.44

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: rs2040932475; hg19: chr16-67465323;