16-67436149-GCC-GCCC

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_000196.4(HSD11B2):c.664+16dup variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,564,162 control chromosomes in the GnomAD database, including 3 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (3 hom.)
• Consequence: HSD11B2 NM_000196.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.349

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 Benign. Variant got -12 ACMG points.

• BP6: Variant 16-67436149-G-GC is Benign according to our data. Variant chr16-67436149-G-GC is described in ClinVar as [Likely_benign]. Clinvar id is 723515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.001 (151/150936) while in subpopulation EAS AF= 0.00293 (15/5118). AF 95% confidence interval is 0.00181. There are 0 homozygotes in gnomad4. There are 78 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.664+16dup		splice_region_variant, intron_variant		ENST00000326152.6
HSD11B2	XM_047434048.1	c.352+16dup		splice_region_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSD11B2	ENST00000326152.6	c.664+16dup		splice_region_variant, intron_variant		1	NM_000196.4	P1
HSD11B2	ENST00000567684.2	n.527+16dup		splice_region_variant, intron_variant, non_coding_transcript_variant		3
HSD11B2	ENST00000566606.1			downstream_gene_variant		5

Frequencies

GnomAD3 genomes AF: 0.000995 AC: 150 AN: 150828 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00292

Gnomad SAS AF: 0.00126

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00121

Gnomad OTH AF: 0.000487

GnomAD4 exome AF: 0.00143 AC: 2024 AN: 1413226 Hom.: 3 Cov.: 36 AF XY: 0.00142 AC XY: 999 AN XY: 703968

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.000981

Gnomad4 ASJ exome AF: 0.0000788

Gnomad4 EAS exome AF: 0.00350

Gnomad4 SAS exome AF: 0.00119

Gnomad4 FIN exome AF: 0.00742

Gnomad4 NFE exome AF: 0.00115

Gnomad4 OTH exome AF: 0.00120

GnomAD4 genome AF: 0.00100 AC: 151 AN: 150936 Hom.: 0 Cov.: 31 AF XY: 0.00106 AC XY: 78 AN XY: 73722

Gnomad4 AFR AF: 0.00107

Gnomad4 AMR AF: 0.000198

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00293

Gnomad4 SAS AF: 0.00126

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00121

Gnomad4 OTH AF: 0.000482

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Apparent mineralocorticoid excess Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 28, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 20, 2023

- -

Computational scores

Source: dbNSFP v4.3

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: rs72650121; hg19: chr16-67470052;