1-209732565-G-C

Position:

• chr1-209732565-G-C

Variant summary

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

The NM_005525.4(HSD11B1):​c.647G>C​(p.Gly216Ala) variant causes a missense change. 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSD11B1 NM_005525.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.20

Genes affected

HSD11B1 (HGNC:5208): (hydroxysteroid 11-beta dehydrogenase 1) The protein encoded by this gene is a microsomal enzyme that catalyzes the conversion of the stress hormone cortisol to the inactive metabolite cortisone. In addition, the encoded protein can catalyze the reverse reaction, the conversion of cortisone to cortisol. Too much cortisol can lead to central obesity, and a particular variation in this gene has been associated with obesity and insulin resistance in children. Mutations in this gene and H6PD (hexose-6-phosphate dehydrogenase (glucose 1-dehydrogenase)) are the cause of cortisone reductase deficiency. Alternate splicing results in multiple transcript variants encoding the same protein.[provided by RefSeq, May 2011]

HSD11B1-AS1 (HGNC:):

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	Protein	UniProt
HSD11B1	NM_005525.4	c.647G>C	p.Gly216Ala	missense_variant	5/6	ENST00000367027.5	NP_005516.1
HSD11B1	NM_001206741.2	c.647G>C	p.Gly216Ala	missense_variant	6/7		NP_001193670.1
HSD11B1	NM_181755.3	c.647G>C	p.Gly216Ala	missense_variant	6/7		NP_861420.1
HSD11B1-AS1	NR_134510.1	n.66+9932C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSD11B1	ENST00000367027.5	c.647G>C	p.Gly216Ala	missense_variant	5/6	1	NM_005525.4	ENSP00000355994.3
HSD11B1	ENST00000367028.6	c.647G>C	p.Gly216Ala	missense_variant	6/7	5		ENSP00000355995.1
HSD11B1	ENST00000261465.5	c.647G>C	p.Gly216Ala	missense_variant	6/7	5		ENSP00000261465.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.647G>C (p.G216A) alteration is located in exon 5 (coding exon 5) of the HSD11B1 gene. This alteration results from a G to C substitution at nucleotide position 647, causing the glycine (G) at amino acid position 216 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	D;D;.
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Uncertain	0.063	D
MutationAssessor	Pathogenic	3.4	M;.;M
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0070	D;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.84
MutPred		0.86		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.71
MPC		0.89
ClinPred		0.99	D
GERP RS		3.6
Varity_R		0.91
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-209905910;