chr16-67435634-A-C

Position:

• chr16-67435634-A-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000196.4(HSD11B2):​c.272A>C​(p.Asp91Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: HSD11B2 NM_000196.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 8.88

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.945

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD11B2	NM_000196.4	c.272A>C	p.Asp91Ala	missense_variant	2/5	ENST00000326152.6
HSD11B2	XM_047434048.1	c.-41A>C		5_prime_UTR_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD11B2	ENST00000326152.6	c.272A>C	p.Asp91Ala	missense_variant	2/5	1	NM_000196.4	P1
HSD11B2	ENST00000567684.2	n.135A>C		non_coding_transcript_exon_variant	2/4	3
HSD11B2	ENST00000566606.1	c.*73A>C		3_prime_UTR_variant, NMD_transcript_variant	2/3	5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Apparent mineralocorticoid excess Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

Apr 20, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.86	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Uncertain	0.78	D
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Pathogenic	0.93
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0060	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.73		Loss of ubiquitination at K96 (P = 0.057);
MVP		0.97
MPC		1.6
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.81
gMVP		0.86

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

LitVar

Other links and lift over

dbSNP: rs1356598056; hg19: chr16-67469537;