rs746362951

Variant names:

• chr1-209706809-G-C
• rs746362951
• NM_005525.4:c.320G>C

Your query was ambiguous. Multiple possible variants found:

• chr1-209706809-G-C
• chr1-209706809-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_005525.4(HSD11B1):​c.320G>C​(p.Gly107Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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: 2.17
• Publications: 0 publications found

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:54053): (HSD11B1 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 2 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 0.95858 (below the threshold of 3.09). Trascript score misZ: 1.7211 (below the threshold of 3.09). GenCC associations: The gene is linked to cortisone reductase deficiency 2, cortisone reductase deficiency.
• BP4: Computational evidence support a benign effect (MetaRNN=0.24086285).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005525.4. 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
	HSD11B1	NM_005525.4	MANE Select	c.320G>C	p.Gly107Ala	missense	Exon 3 of 6	NP_005516.1	X5D2L1
	HSD11B1	NM_001206741.2		c.320G>C	p.Gly107Ala	missense	Exon 4 of 7	NP_001193670.1	P28845
	HSD11B1	NM_181755.3		c.320G>C	p.Gly107Ala	missense	Exon 4 of 7	NP_861420.1	P28845

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSD11B1	ENST00000367027.5	TSL:1 MANE Select	c.320G>C	p.Gly107Ala	missense	Exon 3 of 6	ENSP00000355994.3	P28845
	HSD11B1	ENST00000367028.6	TSL:5	c.320G>C	p.Gly107Ala	missense	Exon 4 of 7	ENSP00000355995.1	P28845
	HSD11B1	ENST00000966146.1		c.320G>C	p.Gly107Ala	missense	Exon 3 of 6	ENSP00000636205.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251256 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.0020	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.018
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.70	T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.24	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.79	N
PhyloP100		2.2
PrimateAI	Benign	0.39	T
PROVEAN	Benign	0.35	N
REVEL	Benign	0.28
Sift	Benign	0.24	T
Sift4G	Benign	0.97	T
Polyphen		0.82	P
Vest4		0.27
MutPred		0.46		Loss of catalytic residue at A106 (P = 0.0858)
MVP		0.61
MPC		0.26
ClinPred		0.40	T
GERP RS		3.2
Varity_R		0.30
gMVP		0.37
Mutation Taster		=59/41	polymorphism

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: rs746362951; hg19: chr1-209880154;