16-67431372-G-A

Position:

• chr16-67431372-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_000196.4(HSD11B2):​c.124G>A​(p.Ala42Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000286 in 1,253,710 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00027 (3 hom.)
• Consequence: HSD11B2 NM_000196.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.753

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011157364).
• BP6: Variant 16-67431372-G-A is Benign according to our data. Variant chr16-67431372-G-A is described in ClinVar as [Benign]. Clinvar id is 1989648.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSD11B2	NM_000196.4	c.124G>A	p.Ala42Thr	missense_variant	1/5	ENST00000326152.6	NP_000187.3
HSD11B2	XM_047434048.1	c.-48+593G>A		intron_variant			XP_047290004.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD11B2	ENST00000326152.6	c.124G>A	p.Ala42Thr	missense_variant	1/5	1	NM_000196.4	ENSP00000316786	P1
	ENST00000567261.1	n.93C>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 62 AN: 149604 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000332

Gnomad ASJ AF: 0.0132

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000119

Gnomad OTH AF: 0.00146

GnomAD3 exomes AF: 0.000958 AC: 42 AN: 43840 Hom.: 0 AF XY: 0.000999 AC XY: 26 AN XY: 26034

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000124

Gnomad ASJ exome AF: 0.00925

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000126

Gnomad OTH exome AF: 0.000730

GnomAD4 exome AF: 0.000268 AC: 296 AN: 1103998 Hom.: 3 Cov.: 31 AF XY: 0.000285 AC XY: 153 AN XY: 536820

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000254

Gnomad4 ASJ exome AF: 0.0117

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000714

Gnomad4 OTH exome AF: 0.00109

GnomAD4 genome AF: 0.000414 AC: 62 AN: 149712 Hom.: 0 Cov.: 31 AF XY: 0.000411 AC XY: 30 AN XY: 73080

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000332

Gnomad4 ASJ AF: 0.0132

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000119

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.000427 Hom.: 0

Bravo AF: 0.000472

ExAC AF: 0.00150 AC: 16

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.022
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.011	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.50	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.2	N
REVEL	Uncertain	0.38
Sift	Benign	0.061	T
Sift4G	Benign	0.44	T
Polyphen		0.80	P
Vest4		0.34
MutPred		0.35		Loss of stability (P = 0.1585);
MVP		0.88
MPC		1.4
ClinPred		0.082	T
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.20
gMVP		0.32

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: rs765574993; hg19: chr16-67465275;