16-67431425-C-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM2 BP4 BP6_Very_Strong BP7 BS1

The NM_000196.4(HSD11B2):c.177C>A(p.Ala59=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000065 in 1,308,508 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: HSD11B2 NM_000196.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.197

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 -12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.18).
• BP6: Variant 16-67431425-C-A is Benign according to our data. Variant chr16-67431425-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 1256385.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.197 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00035 (53/151418) while in subpopulation AFR AF= 0.00121 (50/41352). AF 95% confidence interval is 0.000942. There are 0 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSD11B2	NM_000196.4	c.177C>A	p.Ala59=	synonymous_variant	1/5	ENST00000326152.6
HSD11B2	XM_047434048.1	c.-48+646C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD11B2	ENST00000326152.6	c.177C>A	p.Ala59=	synonymous_variant	1/5	1	NM_000196.4	P1
	ENST00000567261.1	n.40G>T		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.000350 AC: 53 AN: 151418 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000481

GnomAD4 exome AF: 0.0000277 AC: 32 AN: 1157090 Hom.: 0 Cov.: 31 AF XY: 0.0000302 AC XY: 17 AN XY: 563588

Gnomad4 AFR exome AF: 0.00121

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000869

GnomAD4 genome AF: 0.000350 AC: 53 AN: 151418 Hom.: 0 Cov.: 31 AF XY: 0.000392 AC XY: 29 AN XY: 73960

Gnomad4 AFR AF: 0.00121

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000481

Alfa AF: 0.000569 Hom.: 0

Bravo AF: 0.000393

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Sep 22, 2020

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Nov 02, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
Cadd	Benign	16
Dann	Benign	0.95
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs45562134; hg19: chr16-67465328;