16-67431321-C-A

Variant names:

• chr16-67431321-C-A
• NM_000196.4:c.73C>A

Variant summary

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

The NM_000196.4(HSD11B2):​c.73C>A​(p.Arg25Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000363 in 1,101,412 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: 0.0000036 (0 hom.)
• Consequence: HSD11B2 NM_000196.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.01
• 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.73C>A	p.Arg25Ser	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.73C>A	p.Arg25Ser	missense	Exon 1 of 5	ENSP00000316786.5	P80365
	HSD11B2	ENST00000855497.1		c.73C>A	p.Arg25Ser	missense	Exon 1 of 5	ENSP00000525556.1
	HSD11B2	ENST00000855496.1		c.73C>A	p.Arg25Ser	missense	Exon 1 of 5	ENSP00000525555.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000363 AC: 4 AN: 1101412 Hom.: 0 Cov.: 30 AF XY: 0.00000373 AC XY: 2 AN XY: 535930

African (AFR) AF: 0.00 AC: 0 AN: 21868

American (AMR) AF: 0.00 AC: 0 AN: 16410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15768

East Asian (EAS) AF: 0.00 AC: 0 AN: 18594

South Asian (SAS) AF: 0.00 AC: 0 AN: 42058

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20910

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2890

European-Non Finnish (NFE) AF: 0.00000109 AC: 1 AN: 921032

Other (OTH) AF: 0.0000716 AC: 3 AN: 41882

GnomAD4 genome Cov.: 31

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	Uncertain	0.39
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.99	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.0
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.060	N
REVEL	Uncertain	0.41
Sift	Benign	0.14	T
Sift4G	Benign	0.69	T
Polyphen		0.99	D
Vest4		0.34
MutPred		0.37		Loss of MoRF binding (P = 0.0079)
MVP		0.93
MPC		1.5
ClinPred		0.73	D
GERP RS		4.0
PromoterAI		0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.20
gMVP		0.43
Mutation Taster		=78/22	polymorphism

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

hg19: chr16-67465224;