1-209734386-G-C

Variant names:

• chr1-209734386-G-C
• rs41283132
• NM_005525.4:c.744G>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_005525.4(HSD11B1):​c.744G>C​(p.Gly248Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00457 in 1,614,094 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (25 hom.)
• Consequence: HSD11B1 NM_005525.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.384
• Publications: 5 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 1-209734386-G-C is Benign according to our data. Variant chr1-209734386-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.384 with no splicing effect.
• BS2: High AC in GnomAd4 at 409 AD gene.

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.744G>C	p.Gly248Gly	synonymous	Exon 6 of 6	NP_005516.1	X5D2L1
	HSD11B1	NM_001206741.2		c.744G>C	p.Gly248Gly	synonymous	Exon 7 of 7	NP_001193670.1	P28845
	HSD11B1	NM_181755.3		c.744G>C	p.Gly248Gly	synonymous	Exon 7 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.744G>C	p.Gly248Gly	synonymous	Exon 6 of 6	ENSP00000355994.3	P28845
	HSD11B1	ENST00000367028.6	TSL:5	c.744G>C	p.Gly248Gly	synonymous	Exon 7 of 7	ENSP00000355995.1	P28845
	HSD11B1	ENST00000966146.1		c.741G>C	p.Gly247Gly	synonymous	Exon 6 of 6	ENSP00000636205.1

Frequencies

GnomAD3 genomes AF: 0.00269 AC: 410 AN: 152168 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000413

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00466

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00283 AC: 711 AN: 251030 AF XY: 0.00294

Gnomad AFR exome AF: 0.000984

Gnomad AMR exome AF: 0.00211

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000601

Gnomad NFE exome AF: 0.00477

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00476 AC: 6965 AN: 1461808 Hom.: 25 Cov.: 31 AF XY: 0.00464 AC XY: 3371 AN XY: 727202

African (AFR) AF: 0.000777 AC: 26 AN: 33478

American (AMR) AF: 0.00206 AC: 92 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00144 AC: 124 AN: 86256

European-Finnish (FIN) AF: 0.000393 AC: 21 AN: 53410

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5766

European-Non Finnish (NFE) AF: 0.00578 AC: 6432 AN: 1111970

Other (OTH) AF: 0.00382 AC: 231 AN: 60394

GnomAD4 genome AF: 0.00269 AC: 409 AN: 152286 Hom.: 0 Cov.: 32 AF XY: 0.00262 AC XY: 195 AN XY: 74462

African (AFR) AF: 0.000866 AC: 36 AN: 41552

American (AMR) AF: 0.00268 AC: 41 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4834

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00466 AC: 317 AN: 68032

Other (OTH) AF: 0.00284 AC: 6 AN: 2110

Alfa AF: 0.00119 Hom.: 0

Bravo AF: 0.00280

EpiCase AF: 0.00442

EpiControl AF: 0.00575

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	HSD11B1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	3.5
DANN	Benign	0.68
PhyloP100		-0.38
Mutation Taster		=100/0	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: rs41283132; hg19: chr1-209907731;