16-67431290-C-A

Variant names:

• chr16-67431290-C-A
• rs776852403
• NM_000196.4:c.42C>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_000196.4(HSD11B2):​c.42C>A​(p.Leu14Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000179 in 1,116,198 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L14L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000018 (0 hom.)
• Consequence: HSD11B2 NM_000196.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.97
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP7: Synonymous conserved (PhyloP=-1.97 with no splicing effect.

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.42C>A	p.Leu14Leu	synonymous	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.42C>A	p.Leu14Leu	synonymous	Exon 1 of 5	ENSP00000316786.5	P80365
	HSD11B2	ENST00000855497.1		c.42C>A	p.Leu14Leu	synonymous	Exon 1 of 5	ENSP00000525556.1
	HSD11B2	ENST00000855496.1		c.42C>A	p.Leu14Leu	synonymous	Exon 1 of 5	ENSP00000525555.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000179 AC: 2 AN: 1116198 Hom.: 0 Cov.: 30 AF XY: 0.00000184 AC XY: 1 AN XY: 542526

African (AFR) AF: 0.00 AC: 0 AN: 22586

American (AMR) AF: 0.00 AC: 0 AN: 18286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16444

East Asian (EAS) AF: 0.00 AC: 0 AN: 20420

South Asian (SAS) AF: 0.0000237 AC: 1 AN: 42212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 21850

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2990

European-Non Finnish (NFE) AF: 0.00000108 AC: 1 AN: 928684

Other (OTH) AF: 0.00 AC: 0 AN: 42726

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	6.8
DANN	Benign	0.88
PhyloP100		-2.0
PromoterAI		0.13	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs776852403; hg19: chr16-67465193;